HELIOS-expressing human CD8 T cells exhibit limited effector functions

Introduction: The transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T cells. However, information on human HELIOS⁺ CD8 T cells is limited and conflicting.

Methods: In this study, we characterized by flow cytometry and transcriptomic analyses human HELIOS⁺ CD8 T cells.

Results: These T cells primarily consist of memory cells and constitute approximately 21% of blood CD8 T cells. In comparison with memory HELIOS^- T-BET^high CD8 T cells that displayed robust effector functions, the memory HELIOS⁺ T-BET^high CD8 T cells produce lower amounts of IFN-γ and TNF-α and have a lower cytotoxic potential. We wondered if these cells participate in the immune response against viral antigens, but did not find HELIOS⁺ cells among CD8 T cells recognizing CMV peptides presented by HLA-A2 and HLA-B7. However, we found HELIOS⁺ CD8 T cells that recognize a CMV peptide presented by MHC class Ib molecule HLA-E. Additionally, a portion of HELIOS⁺ CD8 T cells is characterized by the expression of CD161, often used as a surface marker for identifying T_C17 cells. These CD8 T cells express T_H17/T_C17-related genes encoding RORgt, RORa, PLZF, and CCL20.

Discussion: Our findings emphasize that HELIOS is expressed across various CD8 T cell populations, highlighting its significance beyond its role as a transcription factor for Treg or exhausted murine CD8 T cells. The significance of the connection between HELIOS and HLA-E restriction is yet to be understood.