Wednesday, July 29, 2015

Exposure to premature inflammatory milieu inhibits antigen receptor signaling in CD4 T cells

It is believed that proper T cell activation require sequential signaling through Signal 1 (e.g. CD3), Signal 2 (e.g. CD28), Signal 3 (e.g. IL-12 or type I IFN induced inflammation). However, occasionally, for example during autoimmune inflammation or immunotherapy, T cells could be exposed to "out-of-order" Signal 3 without Signal 1. So what are the consequences for such exposure for T cells?

New paper in Immunity has provided some answers. Using human T cells derived from patients treated with high dose of IL-2, the authors found that CD4 T cells, but not CD8 T cells, displayed diminished antigen-specific proliferation in mixed MLR or ConA stimulation assays.

Similar results were obtained with human CD4 T cells pre-incubated in vitro with IL-2 prior to MLR assay (that tests Signal 1 activity). One caveat is that the authors have used linear scale to "highlight" the difference in proliferation of treated T cells. However, the proliferation is a geometrical function and ordinarily should be depicted in logarithmic scale.

Next, the authors found that inhibition of Signal 1 by inflammatory milieu was short-lived and quickly recovered if inflammatory milieu was removed.

Similar quick recovery was seen in vivo with mouse OVA-specific OT-II CD4 T cells treated anti-CD40 antibody and IL-2 to mimic inflammatory milieu and later harvested at different time points post treatment.

Mechanistically, the authors showed that Socs3 was selectively up-regulated in CD4 T cells upon exposure to Signal 3 and inhibited STAT5 signaling in CD4 T cells.

In summary, this very simple paper raises very interesting points regarding how T cells computes external signals. As the authors noted Signal 3 could exist in conditions such as systemic autoimmune inflammation and sepsis, or during immunotherapy. How would these conditions affect activation of CD4 T cells?

David Usharauli


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