The Transcription Factor Hobit Identifies Human Cytotoxic CD4+ T Cells

Anna E. Oja, Felipe A. Vieira Braga, Ester B. M. Remmerswaal, Natasja A. M. Kragten, Kirsten M. L. Hertoghs, Jianmin Zuo, Paul A. Moss, René A. W. van Lier, Klaas P. J. M. van Gisbergen, Pleun Hombrink

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.