Cooperative action of CD8 T lymphocytes and natural killer cells controls tumour growth under conditions of restricted T‐cell receptor diversity

Summary In mice expressing a transgenic T‐cell receptor (TCR; TCRP1A) of DBA/2 origin with reactivity towards a cancer‐germline antigen P1A, the number of TCRP1A CD8 + T cells in lymphoid organs is lower in DBA/2 than in B10.D2 or B10.D2(× DBA/2)F 1 mice. This reduction results from haemopoietic cell autonomous differences in the differentiation of the major histocompatibility complex class I‐restricted TCRP1A thymocytes controlled by DBA/2 versus B10.D2‐encoded genes. We report here that the lower number of TCRP1A CD8 + T cells in DBA/2 mice correlated with their poor resistance to P1A‐expressing mastocytoma solid tumours. Functional potency of CD8 + cytolytic T lymphocytes (CTL) from the above strains was not compromised, but their number after expansion appeared to be influenced by their genetic background. Intriguingly, non‐transgenic DBA/2 mice resisted P1A + tumours more efficiently despite poor representation of P1A‐specific CTL. This was partly the result of their more heterogeneous TCR repertoire, including reactivity to non‐P1A tumour antigens because mice that had rejected a P1A + tumour became resistant to a P1A − variant of the tumour. Such ‘cross‐resistance’ did not develop in the TCRP1A transgenic mice. Nonetheless, reconstitution of RAGº / º mice with TCRP1A CD8 + T cells, with or without CD4 + T cells, or exclusive representation of TCRP1A CD8 + T cells in RAGº / º TCRP1A transgenic mice efficiently resisted the growth of P1A‐expressing tumours. Natural killer cells present at a higher number in RAGº / º mice also contributed to tumour resistance, in part through an NKG2D‐dependent mechanism. Hence, in the absence of a polyclonal T‐cell repertoire, precursor frequencies of natural killer cells and tumour‐specific CTL affect tumour resistance.