Intratumoral Convergence of the TCR Repertoires of Effector and Foxp3+ CD4+ T cells

The presence of Foxp3 + regulatory CD4 + T cells in tumor lesions is considered one of the major causes of ineffective immune response in cancer. It is not clear whether intratumoral T reg cells represent T reg cells pre-existing in healthy mice, or arise from tumor-specific effector CD4 + T cells and thus representing adaptive T reg cells. The generation of T reg population in tumors could be further complicated by recent evidence showing that both in humans and mice the peripheral population of T reg cells is heterogenous and consists of subsets which may differentially respond to tumor-derived antigens. We have studied T reg cells in cancer in experimental mice that express naturally selected, polyclonal repertoire of CD4 + T cells and which preserve the heterogeneity of the T reg population. The majority of T reg cells present in healthy mice maintained a stable suppressor phenotype, expressed high level of Foxp3 and an exclusive set of TCRs not used by naive CD4 + T cells. A small T reg subset, utilized TCRs shared with effector T cells and expressed a lower level of Foxp3. We show that response to tumor-derived antigens induced efficient clonal recruitment and expansion of antigen-specific effector and T reg cells. However, the population of T reg cells in tumors was dominated by cells expressing TCRs shared with effector CD4 + T cells. In contrast, T reg cells expressing an exclusive set of TCRs, that dominate in healthy mice, accounted for only a small fraction of all T reg cells in tumor lesions. Our results suggest that the T reg repertoire in tumors is generated by conversion of effector CD4 + T cells or expansion of a minor subset of T reg cells. In conclusion, successful cancer immunotherapy may depend on the ability to block upregulation of Foxp3 in effector CD4 + T cells and/or selectively inhibiting the expansion of a minor T reg subset.