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


  

Signal 1 = Signal 2 = Signal 3?

Occasionally one finds research articles published in the top journals, which rather than simplifying and clarifying the subject matters, make them more confusing. Frequently, even after reading and then re-reading them, one still cannot comprehend the "significance" of the finding.

I have one rule: if I cannot understand an immunology research paper with one read, I blame the editors. The author, of course, wants to publish his/her research in top journal, but it is a responsibility of the editors to be a gatekeepers and to make sure that the article is written in an easy to understand style.

I have another rule: the good data naturally make paper writing and reading easy.

The following paper from journal Science is such a disappointment. It starts strong with FucciRG mice model to track T cells acquiring a quiescent state after active cycling. The rest is confusing. The authors proposed that signal 1 (antigen), signal 2 (co-stimulation), and signal 3 (inflammatory milieu) play equal and quantitatively linear role in imprinting T cell division rate (they called it division destiny (DD), as if it would make it easier to understand). 

First of all, if one takes, for example cytokine IL-2, it not just quantitatively affects the T cell division rate but it qualitatively changes T cell fate and memory potential too. The authors suggestion that IL-2's physiological role is to maintain T cell division at a later stage of activation, at the tissue site, away from priming site (such as spleen or lymph nodes) does not account for IL-2's role in T cell effector class differentiation (CTL, IFN-gamma or IL-2 producers) or memory imprinting. These latter concepts could equally well explain the authors' observation with IL-2 receptor alpha deficient T cells.

I personally would suggest to Science editors to avoid publishing research papers filled with unnecessary models (especially mathematical models) or with one-sided explanations.

David Usharauli