Cooperative action of CD8 T lymphocytes and natural killer cells  controls tumour growth under conditions of restricted T-cell  receptor diversity.
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(x DBA/2)F1 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.
Shanker
Anil
A
Centre d'Immunologie de Marseille-Luminy, Université de Méditerranée, Marseille cedex, France. shankera@mail.nih.gov
Buferne
Michel
M
Schmitt-Verhulst
Anne-Marie
AM
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D048708:Cell Growth Processes; D017637:Clonal Deletion / Q000235:genetics; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008211:Lymphocyte Cooperation; D034801:Mastocytoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics
D000951:Antigens, Neoplasm; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; C507749:cancer-testis antigen P1A, mouse