A Bax‐dependent apoptosis pathway of CD4+CD25highFoxp3+ regulatory T cells is a new therapeutic target in regulation of immune responses

The question of whether T cell responses to more than 2000 serologically‐defined tumor antigens are under regulation of naturally occurring CD4+CD25highFoxp3+ regulatory T cells (nTreg cells) has not been answered. To address this issue, we first identified a HLA‐A2.1‐restricted T cell antigen epitope of self‐tumor antigen CML66L, 66Pa. CML66L was identified in chronic myelogenous leukemia (CML) (Yang et al , PNAS USA, 98:7492, 2001). We found that the HLA‐A2.1/66Pa peptide complex in vitro stimulated the in vivo ‐primed T cells, which suggests that CML66L elicits T cell immune responses. We also developed a novel internal reference epitope for identification of T cell epitopes by construction of chimeric CML66L containing myeloid antigen proteinase 3 epitope Pr1 as a control. In addition, previous reports showed that homeostasis of nTreg cells require CD28 T cell co‐stimulation and interleukin‐2 (IL‐2)/IL‐2 receptor signaling. We demonstrated that anti‐apoptotic proteins, such as Bcl‐x isoforms and their interaction protein translationally controlled tumor protein (TCTP), play a critical role in CD28‐ and IL‐2‐signaled T cell survival pathways (Yang et al , Oncogene 24, 4778, 2005). Thus, we wanted to examine our hypothesis that Bcl‐xL‐interacting, pro‐apoptotic protein Bax mediates the apoptotic pathway in nTreg cells. We found that nTreg cells regulates CD8+ T cell responses to 66Pa, and that depletion of nTreg cells via a proapoptotic protein Bax‐dependent apoptotic pathway enhances CD8+ T cell responses to 66Pa. These findings suggest new therapeutic targets in enhancing anti‐tumor immunotherapy by modulation of survival and homeostasis of nTreg cells.