Le syndrome de Sézary (SS) est un variant leucémique et érythrodermique de lymphomes T cutanés. Il est caractérisé par la présence d’une population clonale de LT CD4+, présentant un noyau cérébriforme atypique, dans la peau, les ganglions lymphatiques et le sang périphérique. Après un bilan clinique, le diagnostic de cette pathologie est confirmé par l’analyse immunohistochimique d'une biopsie cutanée. Néanmoins, la cytomorphologie des cellules de Sézary circulantes n’est pas uniquement associée au SS. Notre laboratoire a identifié CD158k comme marqueur membranaire spécifique des cellules de Sézary. Ce récepteur offre un intérêt dans le diagnostic du SS et dans le suivi de l’évolution de la pathologie. Ainsi, nos résultats montrent qu’un immuno-marquage CD3+ CD158k+, analysé en cytométrie en flux, est une technique spécifique et sensible de détection de la cellule de Sézary par rapport à la cytomorphologie. Alors que dans plus de 30% des cas le SS passe inaperçu durant l’examen cytomorphologique, une analyse en cytométrie en flux permet la mise en évidence de cellules tumorales résiduelles. La présence systématique de CD158k à la surface des cellules de Sézary nous a conduit à rechercher l’expression d’autres KIRs. Sur les lymphocytes tumoraux circulants d’un patient ainsi que sur la lignée cellulaire correspondante, l’expression des formes activatrices et inhibitrices des récepteurs CD158a/h et CD158b/j est détectée. A la différence des lymphocytes NK et T CD8+, le récepteur présentant une fonction inhibitrice (KIR-L) ne l’emporte pas sur celui ayant une fonction activatrice (KIR-S) dans la cellule de Sézary. En fait, les KIR-L, à l’exception de CD158k, sont trouvés non fonctionnels dans la cellule tumorale. Ainsi, l’engagement des formes activatrices CD158h ou CD158j permet une régulation positive de la voie de signalisation CD3-dépendante de JNK et de la prolifération tumorale. Une étude fonctionnelle de la population T CD4+ KIR+, équivalent normal de la cellule de Sézary, a aussi été réalisée. Nous avons mis en évidence une expression préférentielle de la forme activatrice ou inhibitrice des récepteurs KIR homologues, selon le donneur. D’autre part, les KIRs activateurs ou inhibiteurs, exprimés à la surface des LT CD4+, jouent un rôle de co-récepteur vis-à-vis du TCR. Ainsi, une régulation positive ou négative de la prolifération et de la voie de signalisation CD3-dépendante de ERK est observée en fonction du type de récepteur co-engagé. Il est bien établi que les KIR-S s’associent à la molécule adaptatrice KARAP/DAP12 pour la transduction d’un signal d’activation. Dans les cellules T CD4+ saines et tumorales, la protéine recrutée par ces récepteurs est encore non identifiée. Notre étude sur la population T CD4+ CD158j+ de sujets sains montre l’implication de la protéine HS1 dans la signalisation mise en place par le récepteur KIR activateur. La réalisation de ce travail a permis de mieux comprendre les mécanismes mis en place à partir des KIRs dans les cellules T CD4+. Ce travail ouvre de nouvelles perspectives concernant le rôle de ces récepteurs dans les mécanismes permettant l'expansion tumorale des cellules de Sézary / Sézary syndrome (SS) is a leukemic and erythrodermic variant of cutaneous T-cell lymphomas. It is characterized by the presence of a clonal CD4+ T lymphocyte population in the skin, lymphnodes and peripheral blood. After clinical assessment, diagnosis of this disease is confirmed by immunohistochemistry analysis of a skin biopsy. However, the cytomorphology of circulating Sézary cells is not just associated to SS. Our laboratory has identified CD158k as a phenotypic marker for Sézary cells. This receptor can be used in the diagnosis of the SS and in monitoring the evolution of the disease. Our results show that the CD3/CD158k immunostaining, analysed by flow cytométrie, is more specific and sensitive than cytomorphology to detect atypical circulating cells. While more than 30% of the SS is misdiagnosed by the cytomorphologic identification, flow cytometry analysis allows the detection of residual tumor cells. Given the systemic expression of CD158k on Sézary cells, we next investigated the expression of additional KIRs. On circulating malignant lymphocytes from one patient and the corresponding cell line, the expression of inhibitory and activating forms of CD158a/h and CD158b/j receptors was detected. In contrast to NK cells and CD8+ T lymphocytes, the inhibitory receptor signaling (KIR-L) does not outweigh the activating receptor signaling (KIR-S) in the Sézary cell. In fact, KIR-L, except CD158k, are found not functional in the tumor cell. Thus, CD158h or CD158j engagement results in an enhanced CD3-induced cell proliferation and JNK activation. A functional study of CD4+ KIR+ T lymphocyte population, the normal equivalent of Sézary cells, was then performed. We observed an exclusive expression of the activating or the inhibitory form of KIR receptors, depending on the donor. Activating or inhibitory KIRs, expressed on the CD4+ T cell surface, act as coreceptors. Thus, a positive or negative regulation of the CD3-induced cell proliferation and ERK activation is observed by triggering the KIR-S or -L respectively. It is well known that stimulatory KIR initiates intracellular signals through their association with the adaptor protein KARAP/DAP12. However, in normal and malignant CD4+ T cells the protein recruited by these receptors is still not identified. Our study on CD4+ CD158j+ T lymphocyte population from healthy individuals showed the involvement of HS1 protein as a potential adaptor molecule in the activating KIR signaling pathway. This work has provided insight into the mechanisms of KIRs signaling in CD4+ T cells and opens new perspectives on the role of these receptors in proliferation of Sézary cells

Ingeniero Civil / El objetivo general del presente trabajo de título es evaluar la influencia de parámetros geométricos relevantes sobre el comportamiento de conexiones usando perfiles T (Tstub) soldados. El estudio es de carácter teórico y pretende proveer información sobre el comportamiento último de los elementos de conexión. Anteriormente, se han llevado a cabo estudios similares en los que, sin embargo, se utilizaron perfiles laminados, poco comunes en Chile, donde la mayoría son elementos soldados. Se realizaron varios modelos de elementos finitos mediante el programa computacional ANSYS, entre los cuales se hicieron variar los parámetros elegidos. El estudio se centró en tres parámetros: la distancia entre líneas de pernos a tracción, la disposición de los pernos a tracción y el espesor relativo del alma del perfil T con respecto al espesor del ala del perfil T. Después de una pretensión de los pernos, cada modelo fue sometido a una carga estática que se aumentó hasta lograr la falla de uno de los elementos de la conexión, ya sea perno o perfil. La comparación de los diferentes modelos permitió determinar la fuerza de tracción máxima aplicada al momento de la falla, el desplazamiento máximo obtenido, así como la distribución de esfuerzos en la soldadura. Los perfiles T se obtuvieron a partir de perfiles soldados existentes (IN o HN) y por lo tanto consideran soldaduras de filete y no de penetración. En este caso, puesto que la soldadura es el elemento sobre el cual se tiene el menor control, se recomienda un diseño que favorezca una distribución de tensión lo más uniforme posible en la soldadura y a este efecto limitar la fluencia parcial del alma de la T. Para poder aprovechar la ductilidad que puede proveer el alma se recomienda usar soldaduras más resistentes.

Orientador: Maria da Conceição Tavares / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Economia / Made available in DSpace on 2018-07-17T07:07:35Z (GMT). No. of bitstreams: 1 Possas_MarioLuiz_D.pdf: 53822681 bytes, checksum: f3d5e62270f29b1019ea111c8f0fa588 (MD5) Previous issue date: 1983 / Doutorado / Doutor em Economia

Chez les mammifères, les lymphocytes T CD4 sont essentiels à la défense de l’organisme contre des infections par des pathogènes ou le développement de tumeurs. Après activation, les lymphocytes T CD4 naïfs ont la capacité de se différencier en divers lymphocytes T helper (Th1, Th2, Th17…) en fonction des signaux reçus. Le choix du lignage permet d’adapter le phénotype et la fonction des cellules au type de danger détecté. Le processus de différenciation des lymphocytes T helper implique l’établissement de programmes d’expression des gènes distincts. La dynamique et la stabilité de ces programmes sont notamment régulées par l’activité d’éléments cis-régulateurs. Le but de ma thèse était de comprendre les mécanismes épigénétiques qui contrôlent la programmation des lymphocytes T CD4. Dans cet objectif, nous avons étudié le rôle de la H3K9 méthyl-transférase SETDB1 dans la différenciation des lymphocytes T CD4 en Th1 et Th2, deux lignages T helper fortement antagonistes. Nous avons découvert que SETDB1 réprime de manière critique le programme d’expression des gènes Th1. En effet, en l’absence d’expression de Setdb1, la différenciation Th1 est exacerbée. De plus, lorsqu’elles sont exposées à un signal pro-Th1, les cellules Th2 franchissent les barrières de lignage et se transdifférencient en Th1. De manière surprenante, SETDB1 ne cible pas directement les enhancers Th1. Au contraire, l’enzyme dépose de manière type cellulaire spécifique la marque répressive H3K9me3 au niveau d’un set restreint de rétrovirus endogènes (ERVs). Des analyses bio-informatiques ont indiqué que les rétrotransposons ciblés sont fortement associés à des gènes impliqués dans les processus immunitaires. La suite de ces analyses a indiqué que ces ERVs flanquent et répriment l’activité d’éléments cis-régulateurs des gènes Th1, ou agissent eux même comme des enhancers du lignage. En conclusion, la déposition de H3K9me3 par SETDB1 garantit l’intégrité des lymphocytes T helper en réprimant un panel d’ERVs qui ont été exaptés en modules cis-régulateurs pour façonner et contrôler le réseau de gènes Th1. / CD4 T lymphocytes play a central role in the defense of mammal organisms against infections by pathogens and the development of tumors. Upon activation, naïve CD4 T cells differentiate into distinct helper cell subsets depending on environmental cues. T helper cells are key players of the immune system as they finely orchestrate immune responses in a danger-adapted manner. The process of T helper differentiation relies on the establishment of complex and lineage-specific gene expression programs. The dynamics and stability of these programs are regulated at the chromatin level through epigenetic control of cis-regulatory elements. My thesis objective was to investigate the epigenetic pathways involved in the regulation of enhancer activity in CD4 T cells. In this purpose, we studied the role of the H3K9 specific methyltransferase SETDB1 in the differentiation of Th1 and Th2 cells, which are strongly antagonistic. We report that SETDB1 critically represses the Th1 gene expression program. Indeed, Setdb1-deficient naïve T cells show exacerbated Th1 priming. Moreover, when exposed to a Th1-instructive signal, SETDB1-deficient Th2 cells cross lineage boundaries and transdifferentiate into Th1 cells. Surprisingly, SETDB1 does not directly target Th1 enhancers to heterochromatin. Instead, SETDB1 deposits the repressive H3K9me3 mark at a restricted and cell type specific set of endogenous retroviruses, strongly associated with genes involved in immune processes. Further bioinformatic analyses indicated that these retrotransposons flank and repress Th1 gene cis-regulatory elements or behave themselves as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures T cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network.

Seminario de Título para optar al Título de Ingeniera en Biotecnología Molecular. / La función supresora de las células T reguladoras (Tregs) puede tener efectos negativos sobre la respuesta inmune antitumoral. Por lo tanto, es de gran importancia estudiar los factores que alteran la eficiencia de su inhibición, de tal forma de poder mejorar las terapias antitumorales. La alta heterogeneidad de las Tregs periféricas es uno de los problemas que deben ser abordados para mejorar y desarrollar nuevas terapias antitumorales. Dentro del subset de Tregs, nuevos marcadores superficiales para la población T reguladora tipo 1 (Tr1) no-clásica han sido reportados recientemente, permitiendo su identificación mediante la expresión de las moléculas CD49b y LAG-3 en su superficie. El efecto terapéutico de la población identificada mediante estos marcadores ya ha sido estudiado en modelos murinos de diabetes y de artritis inducida por colágeno, en los cuales mostraron un efecto protector. Sin embargo, su rol en el contexto tumoral ha sido poco estudiado. Es por esto por lo que buscamos caracterizar a la población Tr1, identificada mediante la expresión de CD49b, en un modelo murino de melanoma. Sorprendentemente, se encontró que su presencia parece estar fuertemente influenciada por el microambiente en el cual se encuentra. Mientras que en los linfonodos drenantes de tumor (TdLNs) este subset compone tan solo el 4% del total de células T CD4+, en el tumor alcanzan un 30% de las células T CD4+. Por otra parte, las Tregs convencionales Foxp3+ (cTregs), componen alrededor de un 15% de los linfocitos que infiltran el tumor (TILs) que expresan CD4, casi la mitad de lo observado para las Tr1. En cuanto a su fenotipo, se observó que, aunque en menores niveles que las cTregs, alrededor del 50% y 30% de las Tr1 expresan Nrp1, en los TdLNs y en el tumor, respectivamente. Esta molécula es un co-receptor de VEGF, y se ha descrito que es esencial para la estabilidad y función del fenotipo supresor de las cTreg y para la progresión tumoral. Además, se observó que las Tr1 muestran un patrón diferencial de expresión de ciertas moléculas reguladoras, comparado con las cTregs: una mayor intensidad mediana de fluorescencia de la ectonucleotidasa CD73 en el tumor, contrario a lo que se observa en los TdLNs, y una menor producción de IL-10 en el tumor. Se encontró además que la capacidad proliferativa de las cTregs es significativamente mayor a la de las Tr1, tanto en el tumor como en los TdLNs. Así, nuestros resultados destacan las posibles diferencias entre los mecanismos de inmunosupresión de los subsets de Tregs, los cuales pueden variar dependiendo del microambiente (TdLNs versus tumor). / T regulatory cells (Tregs) suppressive function can have a detrimental effect on immune responses against tumor cells. Thus, in order to improve actual anti-tumor therapies, it is of great importance to study the factors altering their inhibition efficiency. The high heterogeneity of peripheral Tregs is one of the problems that have to be addressed to enhance and develop novel anti-tumoral therapies. Within the Tregs subsets, new surface markers for the non-classical type 1 regulatory T cells population (Tr1) have been recently reported, allowing their identification through the expression of the CD49b and LAG-3 molecules. Their therapeutic effect has already been studied in murine models of diabetes and collagen-induced-arthritis, in which they displayed a protective effect. Nevertheless, very few studies have focused on investigating their role in the tumoral context. Thus, we sought to investigate the function of the Tr1 cell subset, identified through the expression of CD49b, in a murine melanoma model. Surprisingly, we found that their presence seems to be strongly influenced by the microenvironment they encounter. Whereas in the tumor draining lymph nodes (TdLNs) this subset composes only around 4% of total CD4+ T cells, in the tumor, they compose almost 30% of CD4+ T cells. On the other hand, conventional Fopx3+ Tregs (cTregs) compose around 15% of CD4+ tumor-infiltrating T cells, almost half of the percentage of Tr1 cells. Regarding their phenotype, we observed that, although in lower levels than cTregs, around 50 and 30% of Tr1 cells express Neuropilin-1 (Nrp1), in the TdLNs and in the tumor, respectively. Nrp1 is a VEGF co receptor, which has been described to be essential for the stability and function of cTregs suppressive phenotype and in tumor progression. Even more, we also observed that Tr1 cells show a differential pattern of expression of some regulatory molecules, compared to cTregs: a higher median fluorescence of the ectonucleotidase CD73 in the tumor microenvironment, contrary to what is seen in the TdLNs, and a lower production of IL 10 in the tumor. Furthermore, we found that the proliferative capacity of cTregs is significantly higher to Tr1 cells, both in the tumor and in the TdLNs. Thus, our results further highlight the possible differences between the immunosuppression mechanisms of the Tregs subsets depending on the microenvironment (TdLNs versus tumor site).

archives@tulane.edu / Effective adaptive immune responses depend on the presentation to CD4+ T cells antigen peptides bound to major histocompatibility complex class II proteins. The structure of an antigen strongly influences its processing within the endolysosome and potentially controls the identity and abundance of peptides that are presented to T cells. The dissertation presented here sought to expand our understanding of how antigen structure and stability influence adaptive immune responses for two model antigens. Pseudomonas exotoxin A domain III (PE-III) functions as an ADP-ribosyltransferase with significant cellular toxicity and has been incorporated into a recombinant immunotoxin for the treatment of cancer. The bacterial component of the PE-III immunotoxin is highly immunogenic and generates neutralizing antibodies that render subsequent treatments ineffective. A group of six single-amino-acid substitutions in PE-III that were predicted to disrupt CD4+ T-cell epitopes have been shown to reduce antibody responses in mice. Here we demonstrate that only one of the substitutions, R494A, exhibits reduced folding stability and proteolytic resistance through the removal of a hydrogen bond. This destabilization significantly reduces its antibody immunogenicity while generating CD4+ T-cell epitopes that are indistinguishable from those of wildtype PE-III. PE-III specific B cells isolated from R494A-immunized animals contained fewer somatic mutations, which are associated with affinity maturation, and exhibited a weaker germinal-center gene signature, compared to B cells from wildtype-immunized animals. Chicken ovalbumin (cOVA) has been studied for decades primarily due to the robust genetic and molecular resources that are available for experimental investigations. cOVA is a member of the serpin superfamily of proteins that function as protease inhibitors, although cOVA does not exhibit this activity. As a serpin, cOVA possess a protease-sensitive reactive center loop that lies adjacent to the OT-II epitope. We took advantage of the previously described single-substitution-variant, OVA R339T, which can undergo the dramatic structural transition observed in serpins to study how changes in loop size and protein stability influences CD4+ T-cell priming in vivo. We observed that OVA R339T loop-insertion increases overall stability and protease resistance and significantly shortens the reactive center loop. This results in reduced CD4+ T-cell priming of the OT-II epitope in SJL mice. These findings have implications for the design of more effective vaccines for the treatment of infectious diseases and cancer as well as the development of more robust CD4+ T-cell epitope prediction tools. / 1 / Daniel Moss

Virtual memory (VM) CD8+ T cells represent a population of antigen-inexperienced T cells with an apparent memory phenotype. In lymphoreplete germ-free mice VM CD8+ T cells represent 10-20% of all peripheral CD8+ T cells. Their origin correlates with the levels of self-reactivity where the main factor that determinates the T-cell fate decision is the strength of homeostatic signals. In the first part of this thesis, we demonstrated that VM CD8+ T cells and naïve CD8+ T cells had distinct TCR repertoire and T-cell subsets contained different clonotypes. Moreover, 'VM clones' were enriched among VM T cells and were also present in naïve T cells. In contrast, 'naïve clones' were almost exclusively detected in naïve T cells. Next, we characterized the signaling of particular OVA-reactive TCRs from both naïve and VM subsets. We confirmed that 6 out of 8 tested TCRs were responsive to Kb-OVA. In the last part of the thesis, we developed and optimized a qPCR-based method for the relative quantification of specific T-cell clonotypes prior to and during the immune response. This method will serve as a tool for studying the biology of particular VM and naïve T-cell subsets and their role during the immune response. Keywords: T-cell receptor, homeostatic signaling, self-reactivity, virtual memory cells, T cells

Pitch and heave are limiting motions when driving at high speed on water. The installation ofa T-foil is an effective solution that reduces these motions. Commercial T-foils are available,but today none of them are non-magnetic. This thesis studies the possibility to design anon-magnetic T-foil that can carry the considerable loads that such a constructionexperiences. The T-foil is designed for vessels such as the Visby Class corvette. Vortex lattice theory is used to calculate the pressure distribution acting on the construction atdifferent load cases. Required laminate thickness is determined by iteration using a linearfinite element model of the fin. The conclusion is that it is possible to manufacture a non-magnetic T-foil of the required size.A critical area in the construction is the T-joint between the vertical strut and the horizontalfoil. Future investigations should include laboratory tests of the T-joint as well as moredetailed hydrodynamic analysis for more accurate input parameters of the T-foil. / NR 20140804

Thymic negative selection has been identified as a crucial checkpoint in thymocyte development that purges the T-cell repertoire of autoreactive T cells through apoptosis of the cells after strong T cell receptor (TCR) stimulation. It has been well established that efficient thymic negative selection is required to prevent severe monogenic autoimmune diseases, such as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. The involvement of negative selection in other T cell-mediated autoimmune diseases remains unclear. This is largely due to the lack of fully-humanized physiological models for the study of human thymic negative selection. In the work presented here, I aim to study human thymic negative selection in healthy control (HC) immune systems and to determine whether negative selection is impaired in immune systems from individuals with Type 1 diabetes (T1D), a T cell-mediated autoimmune disease. To facilitate these studies, I developed novel humanized mouse and organ culture models. These models built on the previously described Personalized Immune (PI) mouse model [1]. The PI mouse model allows for the rederivation of a fully humanized immune system from a human donor by transplanting hematopoietic stem cells (HSC) and progenitors from an individual adult donor and a human fetal thymus fragment to immunodeficient mice. The HSCs then reconstitute all immune cell lineages, including T cells which develop in the human thymus fragment. This model is extremely powerful because it allows for the study of a human’s immune system in a model that is conducive to experimental replicates and interventions, unlike studies done directly on human patients. To optimize this model for the study of thymic negative selection, I developed two other PI models. The first is the TCR-transgenic PI thymic organ culture (TOC) model. This model allows for the study of the selection of a specific TCR in a culture system combining human HSCs and thymus fragments. The second model is the TCR-transgenic PI mouse model. This model allows for the study of the thymic selection of a specific TCR in a fully humanized in vivo model. The work presented here utilized these three powerful PI models to interrogate the thymic negative selection process in human health and disease at a depth not previously possible. Using these models, we demonstrated the first evidence for thymic negative selection of an insulin-reactive TCR that recognizes a naturally expressed antigen in healthy human immune systems. These studies also demonstrated that robust negative selection requires HSCs expressing the HLA-restriction element of the TCR, and without the expression of that HLA on HSCs, negative selection is reduced and performed in later stages of thymic development. When comparing the phenotypic and functional characteristics of thymocytes undergoing negative selection in HC and T1D immune systems, T1D thymocytes in some immune systems had differential expression of TCR-signaling and negative selection markers and resistance to apoptosis and cell death after strong TCR stimulation. Studies on the negative selection of a specific insulin-reactive TCR in healthy and T1D immune systems demonstrated that in healthy immune systems central tolerance to this TCR involved a combination of negative selection and T regulatory cell conversion. This is the first demonstration of combined tolerogenic induction in the human immune system. In contrast, some T1D immune systems demonstrated impaired negative selection of this insulin-reactive TCR and impaired conversion of these autoreactive T cells to T regulatory cells. Further, when comparing the gene expression profile of HC and T1D thymocytes undergoing negative selection, there are multiple genes important in thymic selection and apoptosis that are differentially regulated. Overall, this data provides unique insights into the process of thymic negative selection in healthy immune systems. It also provides the first evidence that thymic negative selection is impaired in some T1D immune systems and this impairment is possibly driven by differential gene expression. The models developed will allow for further study into human thymic selection in health and disease. These findings answer the important question of whether thymic negative selection is impaired in autoimmune disease, which has been debated in the field of T1D research and the wider immunology field. More importantly, it opens the door to targeting of the thymic negative selection pathway with therapeutics for T1D and other autoimmune diseases.

Kutane CD8+ T-Zell-Lymphome beinhalten heterogene Subgruppen mit unterschiedlicher klinischer und histologischer Präsentation. Zytotoxische CD8+ T-Zell-Lymphome sind selten und daher nur ungenügend charakterisiert. Unser Ziel war es, zytotoxische Lymphominfiltrate, basierend auf histologischen, immunphänotypischen und klinischen Faktoren, besser charakterisieren sowie daraus mögliche diagnostische und prognostische Marker abzuleiten zu können. Formalin fixierte und in Paraffin eingebettete Biopsien von 44 Patienten mit kutanen zytotoxischen T-Zell-Lymphominfiltraten wurden aus den Archiven des Instituts für Pathologie und des dermatohistologischen Labors der Klinik für Dermatologie, Venerologie und Allergologie des Universitätsklinikums Würzburg vom Zeitraum 1998 bis 2014 herausgesucht. Histologische, immunphänotypische and molekulargenetische Eigenschaften wurden analysiert und mit den klinischen Daten verglichen. Die identifizierten Fälle der kutanen CD8+ zytotoxischen Lymphominfiltrate (n=44) beinhalteten 1 Fall mit einem aggressiven epidermotropen CD8+ T-Zell-Lymphom (AETCL), 14 Fälle mit einer Mycosis fungoides (MF)/ einem Sézary-Syndrom (SS), 3 Fälle mit einer Lymphomatoiden Papulose (LyP), 5 Fälle mit einem akralen CD8+ T-Zell-Lymphom (akrales CD8+ TCL) and 4 Fälle mit einem subkutanen Panniculitis-artigem T-Zell-Lymphom (SPTCL). 9 Fälle wurden als primär kutanes peripheres T-Zell-Lymphom, nicht näher spezifiziert (cPTCL-NOS) und 4 Fälle als systemisches T-Zell-Lymphom (sPTCL-NOS) klassifiziert. Multiple Hautläsionen, die ein höheres Tumorstadium implizieren, ein hoher Proliferationsindex und die finale Subtyp-Zuteilung zu systemischen PTCL-NOS oder AETCL stellten negative prognostische Faktoren dar. Auf der anderen Seite indizierte ein geringer Proliferationsindex zusammen mit der Expression von CD68 einen indolenten klinischen Verlauf und charakterisierte den Subtyp des akralen CD8+ T-Zell-Lymphoms. Eine enge Korrelation der klinischen Charakteristika mit der Histologie und dem Immunphänotyp ist zur endgültigen Diagnosestellung unbedingt notwendig. / Cutaneous CD8+ lymphoma infiltrates comprise heterogeneous subgroups with diverse clinical and histological presentation. Cytotoxic CD8+ T-cell lymphomas are only rarely encountered and, thus, remain only poorly characterized. Our aim was to obtain proper subtype assignment of CD8+ skin lymphoma infiltrates and to derive putative prognostic markers thereof. Formalin-fixed and paraffin-embedded (FFPE) tissue of 44 patients with CD8+ cytotoxic cutaneous T-cell lymphoma infiltrates was retrieved from the archives of the Institute of Pathology and the Department of Dermatology, University Hospital Wuerzburg, dating back from 1998 until 2014. Cytological, histological, immunohistochemical and molecular genetic features were assessed and correlated with respective clinical data. The identified cases of CD8+ cytotoxic atypical lymphoproliferative infiltrates of the skin (n=44) comprised 1 case of aggressive epidermotropic primary cutaneous T-cell lymphoma (AETCL), 14 cases of mycosis fungoides (MF)/Sézary-syndrome (SS), 3 cases of lymphomatoid papulosis (LyP), 5 cases of acral CD8+ T-cell lymphoma (acral CD8+ TCL) and 4 cases of subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Moreover, 9 cases were classified as primary cutaneous peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and 4 cases as systemic PTCL-NOS. Multiple skin lesions, a high proliferative index and especially a final subtype attribution to AETCL or systemic PTCL-NOS were associated with a worse survival. Coexpression of CD68 by tumour cells was exclusively observed in acral CD8+ T-cell Lymphoma and, thus, indicated an invariably benign clinical course. A thorough clinicopathological correlation with respective staging examinations remains the mainstay for correct subtype assignment and proper prognostication.