Sunday, January 27, 2013

CD4 T cells with killer instincts

CD4 T cells with killer instincts

These two, back to back papers from Nature Immunology caught my attention this week (12). Both papers deal with CD4 T cells that acquire "abnormal" CD8 T cell functions. It has been known for some time that occasionally CD4 T helper cells can show cytotoxic potential or that some tissues, for example, intestinal tissue harbors hybrid population positive for both CD4 and CD8.

To understand the origin of this double positive T cell population, the authors developed reporter mice expressing Thpok-GFP and Runx3-YFP. Transciption factors Thpok and Runx3 control CD4 T helper and CD8 T cytotoxic cell developmental program s respectively. First finding was that unlike spleen CD4 T cells, more than 50% of intestinal CD4 T cells are Thpok-low and express CD8-alpha, granzyme B and CD107a, all markers of cytotoxic T cells. Runx3-YFP reporter mouse confirmed that this CD4 killer cells express Runx3. Importantly, the authors showed that development of double positive T cells was dependent of TGF-beta and vitamin A signaling in T cells. Next, using Rosa26-YFP / Thpok-cre reporter mouse model, they showed that Thpok-low CD4 T cell population developed from Thpok-high population. Next, the authors showed that sorted Thpok-high CD4 T cell upon adoptive transfer into RAG KO mice lost Thpok expression specifically in the gut, but not in spleen or lymph nodes. At the genomic level, the authors showed that conditional deletion of Thpok silencer abrogated acquisition of cytotoxic phenotype by CD4 T cells by stabilizing Thpok. Interestingly, CD4 killer cells do not develop in germ-free mice and deficiency of MyD88 had no effect. Oral feeding with ovalbumin antigen led to the accumulation of OT-II CD4 killer T cells in the gut that express low level of Thpok. Interestingly, regulatory CD4 T cells expressing Foxp3 also developed in similar conditions (after oral feeding). At this stage it is not known what determines this difference. Interestingly, absence of TGF-beta signaling in OT-II cells drove development of severe diarrhea in these mice after oral feeding with ovalbumin, compared to wild-type control. However this mouse also showed deficiency in Foxp3 T cell development, so interpretation of these data is complicated by this fact. These studies showed that Thpok expression was necessary for intestinal damage by Th17 cells in adoptive transfer model and that Runx3 expression counteracted this effect with the help from TGF-beta and retinoic acid.

While these authors suggest that they identify unique T cell population, I would rather call it adaption to local tissue environment. At this stage it is not clear what is the advantage of having CD4 killer cells in the gut or what are their physiological function. They may be needed to maintain local tolerance to commensal microbiota. One interesting observation is that they still maintain class II restriction implying that function of CD8-alpha may be just a by-product of the transcriptional switch.