The Transcription Factor Hobit Identifies Human Cytotoxic CD4⁺ T Cells

The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4⁺ T cells that conforms to the phenotype of cytotoxic CD8⁺ T cells has received increased recognition. These cytotoxic CD4⁺ T cells display constitutive expression of granzyme B and perforin at the protein level and mediate HLA class II-dependent killing of target cells. In humans, this cytotoxic profile is found within the human cytomegalovirus (hCMV)-specific, but not within the influenza- or Epstein-Barr virus-specific CD4⁺ T cell populations, suggesting that, in particular, hCMV infection induces the formation of cytotoxic CD4⁺ T cells. We have previously described that the transcription factor Homolog of Blimp-1 in T cells (Hobit) is specifically upregulated in CD45RA⁺ effector CD8⁺ T cells that arise after hCMV infection. Here, we describe the expression pattern of Hobit in human CD4⁺ T cells. We found Hobit expression in cytotoxic CD4⁺ T cells and accumulation of Hobit⁺ CD4⁺ T cells after primary hCMV infection. The Hobit⁺ CD4⁺ T cells displayed highly overlapping characteristics with Hobit⁺ CD8⁺ T cells, including the expression of cytotoxic molecules, T-bet, and CX3CR1. Interestingly, γδ⁺ T cells that arise after hCMV infection also upregulate Hobit expression and display a similar effector phenotype as cytotoxic CD4⁺ and CD8⁺ T cells. These findings suggest a shared differentiation pathway in CD4⁺, CD8⁺, and γδ⁺ T cells that may involve Hobit-driven acquisition of long-lived cytotoxic effector function.