Positive and negative selection of antigen-specific B cells in transgenic mice expressing variant forms of the V(H)1 (T15) heavy chain

Four variant forms of the V1 (T15-H chain) gene are synthesized in mice. Each V1 variant pairs with a distinct L chain to produce a binding site having specificity for phosphocholine (PC), Transgenic mice expressing variant forms of the V1 gene were analyzed to elucidate the factors driving a cell selection into the peripheral repertoire. In all four lines of H chain transgenic mice analyzed, transgene expression caused complete allelic exclusion of endogenous H chains in the bone marrow (BM), whereas most splenic B cells expressed endogenous H chains. The number of sigM(+) BM a cells and their sig receptor number was reduced compared to that of normal transgene-negative controls, suggesting that a cells expressing transgene-encoded H chains were being negatively selected in the BM, Mice expressing autoreactive forms of the V1 transgene with lower affinity for PC (M603H and M167H) exhibit positive selection of PC-specific a cells into the spleen, whereas mice expressing the higher affinity T15H variant exhibited elevated PC-specific a cells in the peritoneal cavity but few V(H)1(+) splenic a cells. These data suggest that the higher affinity T15-id(+) B cells preferentially survive in the peritoneal cavity, When these H chain transgenes were crossed into the mu MT knockout mouse in which surface expression of endogenous H chains is blocked, the percent of splenic V(H)1(+) PC-specific B cells increased up to 5-fold and T15-id(+) a cells were detectable in the spleen of T15H mice. This implies that T15-id(+) PC-specific a cells can be selected into the periphery, but they compete poorly with follicular a cells expressing endogenous Ig. [References: 58]

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