TCR repertoire and Foxp3 expression define functionally distinct subsets of CD4+ regulatory T cells.

Despite extensive research efforts to characterize peripheral regulatory T (T(reg)) cells expressing transcription factor Foxp3, their subset complexity, phenotypic characteristics, TCR repertoire and Ag specificities remain ambiguous. In this study, we identify and define two subsets of peripheral T(reg) cells differing in Foxp3 expression level and TCR repertoires. T(reg) cells expressing a high level of Foxp3 and TCRs not used by naive CD4(+) T cells present a stable suppressor phenotype and dominate the peripheral T(reg) population in unmanipulated mice. The second T(reg) subset, expressing a lower level of Foxp3 and using TCRs shared with naive CD4(+) T cells constitutes a small fraction of all T(reg) cells in unmanipulated mice and enriches T(reg) population with the same Ag specificities as expressed by activated/effector T cells. This T(reg) subset undergoes extensive expansion during response to Ag when it becomes a major population of Ag-specific T(reg) cells. Thus, T(reg) cells expressing TCRs shared with naive CD4(+) T cells have a flexible phenotype and may down-regulate Foxp3 expression which may restore immune balance at the conclusion of immune response or convert these cells to effector T cells producing inflammatory cytokines.

[The role of nuclear receptors in cell death]. / Rola receptorów jadrowych w procesie smierci komórek.

The nuclear receptors form a group of structurally homologous proteins which act as ligand-dependent transcription factors and regulate a variety of intracellular processes. The nuclear receptors act as monomomers, homodimers, or heterodimers together with retinoid X receptor (RXR). They bind in the nucleus to a specific nucleotide sequence in the promoter region called the response element (RE). Certain nuclear receptors (e.g. Nur77, GR, RXR, RAR, VDR, PPAR) can influence apoptosis through the induction of pro- and/or anti-apoptotic proteins or affect other transcription factors. Some ligands for the nuclear receptors (mainly retinoids) are applied in anticancer therapy alone or in combination with other anticancer drugs.

H-ras up-regulates expression of BNIP3.

BACKGROUND: Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3) is a key regulator of cell death/autophagy and can act as an effector of a necrosis-like, atypical death program. It was implicated in execution of cell death induced by cluster of differentiation 47 (CD47). Despite the postulated role of BNIP3 in the regulation of survival of cancer cells, the influence of oncogenic transformation on BNIP3 expression is unclear. MATERIALS AND METHODS: The influence of oncogenic transformation on expression of BNIP3 was studied using H-ras-transformed cells. The consequences of BNIP3 expression for sensitivity to CD47-mediated cell death were assessed using tetrazolium salt-based assay. RESULTS: Here, the enforced and endogenous expression of Ras coincided with the up-regulation of BNIP3 across a wide spectrum of cancer cells, providing the first experimental evidence that BNIP3 is a regulatory target of H-Ras. This indicated that merely the introduction of a single oncogene may result in the up-regulation of BNIP3. The consequences of CD47 ligation strongly depended on the BNIP3 presence, which in turn correlated with Ras expression. Interestingly, the indirect effect of that phenomenon was the selective sensitivity of Ras-transformed cells to CD47-mediated cell death.

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.