Identification of a mouse mutant with highly deficient cytotoxic T cell memory generation using ENU-induced genome-wide mutagenesis (85.7)

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Abstract While much has been learned about CTL memory maintenance, much remains to be learned on the early events of CTL activation or induction phase. Through an ENU-induced genome-wide mouse mutagenesis program, we screened G3 mice using CD44 expression on CD8+ T cells as a surrogate indicator of the relative representation of the CTL memory subset. One such identified mutant (P-054) has highly deficient CD44hi subset within CD8+ T cells but normal CD44hi subset in CD4+ T cells. An affected male mouse was bred to normal females to generate F1 mice that all had normal numbers of CTL memory subset based on CD44 expression. Random intercross of F1 mice generated CTL deficienct F2 mice at a ratio of ~25%, indicating heritability of this trait and recessive transmission. Linkage of the mutant gene has been established to chromosome 4 to within a region of ~30 genes. The mutant mouse (H-2b) was immunized by BALB.B spleen cells (H-2b) and CTL memory T cells were identified by H60 (a BALB/c-encoded minor histocompatibility ag)-sepcific CTL by appropriate pentamers and a highly deficient H60-specific CTL response was seen. Adoptive transfer of 2C TCR tg CD8+ T cells activated in the presence of added IL-4, a condition known to promote strong CTL memory generation, into P-054 mice resulted in potent maintenance of 2C memory T cells. Thus, P-054 can provide an environment required to maintain known memory CD8+ T cells and likely represents a novel mutant model that is deficient in the induction phase of CTL memory generation.