The latter alterations may promote autoreactivity, while reducing humoral immunity to pathogens, and contribute to the immune dysfunctions seen in old age. Acknowledgments We thank all members of the Riley laboratory past and present and our collaborators, Dr. In old age, B cell development may progressively be diverted into a preBCR-compromised pathway. These abnormalities in B sAJM589 lymphopoiesis likely contribute to the poor humoral immunity seen in old age. is usually critically dependent on the predominance of a particular anti-PC-specific antibody which utilizes the germ line-encoded T15 idiotype and provides high affinity antibodies for clearance of this pathogen [52, 53]. In old mice, titers of anti-PC antibodies elicited by are robust; however, the low affinity and lack of the T15 idiotype exhibited by these antibodies impair their efficacy. Surprisingly, the frequency of T15+ splenic B cells responsive to PC actually increases by ~ threefold in aged mice [52]. However, in old mice, the splenic B cells responsive to PC that are T15? show a sAJM589 ~fivefold increase in frequency [52]. Consequently, while a majority of PC responsive B cells in young adult spleen are T15+, in old mice, a majority of splenic anti-PC-specific B cells are lower affinity T15? clonotypes. The alterations seen in the splenic PC responsive B cell repertoire in old mice appear to have their origins in the old bone marrow sAJM589 [54]. Comparable increases in T15? anti-PC B cell clonotypes are also observed at very early immature B cell stages within the bone marrow of aged mice. This strongly suggests that the alterations in the antibody repertoire to PC in old mice occur as a consequence of abnormalities in B cell development within the bone marrow. Whether alterations occur in more clonally diverse antibody responses in old age is not known. The antibody repertoires specific for the influenza PR8 hemagglutinin protein as well as to the hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) are similarly diverse in young and old mice [55, 56]. However, in humans, the diversity of the antibody repertoire contracts in the elderly and this correlates significantly with poor health [57]. Compromise of the pre-B cell receptor contributes to B cell repertoire reshaping in old age As discussed above, the expression of the SLC proteins, which together with heavy chain comprise the preBCR, is usually substantially reduced in pro-B cells from aged mice. The role of the preBCR sAJM589 in selecting the Rabbit polyclonal to Ataxin3 heavy chain repertoire, based on the differential binding of individual heavy chains to SLC, has been investigated using mice deficient in SLC expression. Young adult mice which lack the SLC generate early pre-B cells; however, since these early pre-B cells fail to express the preBCR, proliferation is usually curtailed at this developmental stage, and numbers of late-stage pre-B cells are substantially reduced [13]. Moreover, pre-B cells from SLC-deficient mice are enriched for heavy chains that cannot associate with SLC [58C61]. Whether the SLC-low B cell precursors in aged bone marrow now show a relaxed preBCR selection of heavy chains remains to be directly tested. The preBCR checkpoint has been shown to function in tolerance sAJM589 to self-antigens [62]. Studies of the newly generated, immature B cell populations in the bone marrow of old mice exhibit unique characteristics suggestive of self-reactivity. These include an increase in the proportion of bone marrow immature B cells that expressed the surface antigen CD43/S7, often co-expressed with CD5, CD11b, and/or PD-1all surface proteins associated with dampening B cell activation and in maintaining anergy and B cell tolerance [63]. Further studies established that the remaining pre-B cell pool in aged mice retained the capacity to generate CD43/S7+ new B cells, but were deficient in precursors of the more conventional CD43/S7? immature B cells [63]. Comparable disparities in the production of CD43/S7+ versus CD43/S7? immature B cells were seen in experiments using B cell precursors from young adult 5 gene knockout mice [63]. This suggests that the CD43/S7+ immature B cells are generated predominantly when preBCR signaling is usually diminished. Both new B cells derived from precursors from either aged mice or 5-deficient young mice had relatively high expression of dual / light chain isotypes indicative of light chain receptor editing or receptor dilution [63]. Moreover, the majority of CD43/S7+ immature bone marrow B cells, in either young or aged mice, were anergic as evidenced by poor mobilization of calcium upon BCR ligation (Alter et. al., manuscript in preparation). Taken together, these findings indicate that when SLC is usually low and preBCR function compromised, disproportionately the new B cells generated express a phenotype associated with.