T lymphocytes of the strain BALB/cHeA exhibit a low proliferative response to IL-2 and a high response to the anti-CD3 monoclonal antibodies, while the strain STS/A lymphocyte response to these stimuli is the opposite. We analyzed the genetic basis of this strain difference, using a novel genetic tool: the recombinant congenic strains (RCS). Twenty BALB/c-c-STS/Dem (CcS/Dem) RCS were used, each containing a different random set of approximately 12.5% of the genes from STS and the remainder from BALB/c. Consequently, the genes participating in the multigenic control of a phenotypic difference between BALB/c and STS become separated into different CcS strains where they can be studied individually. The strain distribution patterns of the proliferative responses to IL-2 and anti-CD3 in the CcS strains are different, showing that different genes are involved. The large differences between individual CcS strains in response to IL-2 or anti-CD3 indicate that both reactions are controlled by a limited number of genes with a relatively large effect. The high proliferative response to IL-2 is a dominant characteristic. It is not caused by a larger major cell subset size, nor by a higher level of IL-2R expression. The response to anti-CD3 is known to be controlled by polymorphism in Fc gamma receptor 2 (Fcgr2) and the CcS strains carrying the low responder Fcgr2 allele indeed responded weakly. However, as these strains do respond to immobilized anti-CD3, while the STS strain does not, and as some CcS strains with the BALB/c allele of Fcgr2 are also low responders, additional gene(s) of the STS strain strongly depress the anti-CD3 response. In a backcross between the high responder and the low responder strains CcS-9 and CcS-11, one of these unknown genes was mapped to the chromosome 10 near D10Mit14. The CcS mouse strains which carry the STS alleles of genes controlling the proliferative response to IL-2 and anti-CD3 allow the future mapping, cloning, and functional analysis of these genes and the study of their biological effects in vivo.

Institute of Molecular Genetics Academy of Sciences Czech Republic Prague

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