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The present work concerns the regulation of B cell activation, growth and terminal differentiation of helper T cells. T cell dependent (TD) B cell activation requires physical cell to cell contact between competent helper T cells (TH) and B cells and the recognition of MHC Class II antigens. The involvement of immunoglobulin receptors in TD B cell induction and maturation of B cells to plasma cells, however, are still unclear. Long term helper T cell lines and clones were raised against naturally expressed minor transplantation antigens. Using such antigen specific TH lines and clones, the mechanisms controlling growth and maturation of B cells to plasma cells were studied. Specific TH cells against both H-Y and C3H/Tif "minor" antigens were able to polyclonally induce small, resting B lymphocytes to proliteration and high rate antibody secretion. This observation definitively excludes an obligatory role of membrane immunoglobulin molecules in TD B cell triggering. In contrast to other similarly derived TH clones, a variant clone, was isolated which was fully competent to activate B cells to proliferation but did not induce PFC in T cell depleted "target" spleen cells. This defect could, however, be fully reconstituted by cell culture supernatants derived from competent TH clones (but not from the variant clone). These results indicated the presence of two distinct factors in such supernatants, controlling either growth or maturation in TD B cell responses, and lead to further efforts in their characterization. A B cell growth factor (BSF-pI) derived from such supernatants, with a Mr of 15-20 kD, displayed no mitogenicity on small, resting B lymphocytes and failed to induce PFC in prol iterating B cells. On the other hand, two distinct species of B cell maturation factors (BMA) were separated from the supernatants with Mr of 60 kD and 30 kD, respectively. These factors induced PFC of several antibody isotypes in assays were only maturation activity was limiting, but only the 60 kD species induced Ig-secretion, in pure populations of lymphoma cells (WEHI-279.1). Finally, neonatal B cells were shown to be inducible to growth but not to immunoglobulin secretion by competent TH cells, in the absence of suppressive effects in the neonatal spleen cell population. These results suggest that "early" B lymphocytes are intrinsically defective in the reception or processing of maturation signals. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1984, härtill 5 uppsatser</p> / digitalisering@umu

Acetyl-CoA Synthase (ACS) katalysiert die Reaktion eines Methylkations, Kohlenstoffmonoxid und CoA zu Acetyl-CoA. Das aktive Zentrum von ACS ist ein Ni,Ni-[4Fe4S]-Cluster (A-cluster), in dem zwei Nickel-Ionen mit einem kubanen [4Fe4S]-Cluster verbrückt sind. An der Biosynthese von komplexen Metallclustern sind in der Regel mehrere akzessorische Proteine, auch Maturationsfaktoren genannt, beteiligt. Die Biosynthese des A-Clusters wurde bisher noch nicht genauer untersucht und es war nicht bekannt welche Proteine die Biosynthese des A-Clusters katalysieren. In dieser Arbeit wurde das Protein AcsF als Maturationsfaktor der ACS identifiziert und seine biochemischen und strukturellen Eigenschaften wurden charakterisiert. AcsF und apoACS aus Carboxydothermus hydrogenoformans bilden einen stabilen Komplex, der zwei Nickel-Ionen binden kann. ApoACS hingegen kann unter den gleichen Bedingungen im Durchschnitt nur weniger als ein Nickel-Ion binden. Der Ni-ACS-AcsF Komplex, an dem zwei Nickel-Ionen gebunden sind, ist katalytisch jedoch nicht aktiv. Erst durch Zugabe von Mg-ATP kann die inaktive Spezies in eine aktive Form überführt werden. AcsF-Proteine gehören zur gleichen Protein-Familie wie CooC-Proteine, die Maturationsfaktoren der Kohlenstoffmonoxid Dehydrogenase. Ein Sequenzähnlichkeitsnetzwerk konnte zeigen, dass AcsF- und CooC-Proteine jeweils eine eigene Untergruppe in dieser Familie bilden. Die AcsF-Proteine von C. hydrogenoformans und Archaeoglobus fulgidus wurden kristallisiert und deren Kristallstrukturen gelöst. Durch einen Vergleich der Strukturen von AcsF mit den Strukturen von zwei CooC-Proteinen konnte aufgedeckt werden, dass die größten strukturellen Unterschiede zwischen AcsF- und CooC-Proteinen zwischem dem Switch I Motif und dem CXC Motif zu finden sind. / Acetyl-CoA synthase (ACS) catalyzes the reaction of a methyl cation, carbon monoxide and CoA to acetyl-CoA. The active site of ACS is a Ni,Ni-[4Fe4S] cluster (A-cluster), in which two nickel ions are bridged to a cubane-type [4Fe4S] cluster. Usually, several accessory proteins are involved in the biosynthesis of such complex metal clusters. However, the biosynthesis of the A-cluster had not yet been investigated and it was not known which accessory proteins take part in its assembly. In this work, the protein AcsF was identified as a maturation factor of ACS, and its biochemical and structural properties were characterized. AcsF and apoACS from Carboxydothermus hydrogenoformans form a stabile complex, that can bind two nickel ions. ApoACS alone, on the other hand, binds on average only less than one nickel ion under the same conditions. The Ni-ACS-AcsF complex, that contains two nickel ions, is not active, but the addition of Mg-ATP converts the inactive species into an active form. AcsF proteins belong to the same protein family as CooC proteins, the maturation factors of carbon monoxide dehydrogenase. A sequence similarity network showed that AcsF and CooC proteins each form their own subgroup within this family. The AcsF proteins from C. hydrogenoformans and Archaeobglobus fulgidus were crystallized and their crystal structures were solved. A comparison of the crystal structures of AcsF proteins with the structures of two CooC proteins revealed that the main structural differences between AcsF and CooC proteins can be found between the switch I motif and the CXC motif.