Protective low avidity anti-tumour CD8+ T cells are selectively attenuated by regulatory T cells

Regulatory T cells (Treg) play a major role in the suppression of protective anti-tumour T cell responses. In the CT26 BALB/c murine model of colorectal carcinoma, Tregs differentially suppress responses to two characterised CD8+ T epitopes, AH1 and GSW11, which results in an absence of detectable IFN-{gamma} producing GSW11- specific T cells in the spleen and lymph nodes of tumour challenged mice. Activation of GSW11-specific T cells correlates with protection against tumour growth. Here we show that GSW11-specific T cells are in fact induced in Treg-replete, CT26-bearing mice, where they make up the majority of tumour infiltrating CD8+ lymphocytes, but exhibit a dysfunctional exhausted phenotype. This dysfunctional phenotype is induced early in the anti-tumour response in draining lymph nodes, spleens and tumours and is significantly more pronounced in GSW11-specific T cells compared to other tumour-specific T cell responses. Depletion of Tregs prior to tumour challenge significantly reduces the induction of exhaustion in GSW11-specific T cells and correlates with altered T cell receptor (TcR) usage. Moreover, the avidity of GSW11- specific TcRs that expanded in the absence of Tregs was significantly lower compared to TcRs of cytotoxic T lymphocyte (CTL) populations that were diminished in protective anti-tumour responses. This indicates that Tregs suppress the induction of protective anti-tumour T cell responses and may signify that the induction of low avidity T cells, while being more susceptible to exhaustion are the most efficacious in tumour rejection.