Thursday, February 4, 2016

Some anergic T cells are precursors for Foxp3+ Tregs

T cell anergy is defined as T cell non-responsiveness to [secondary] antigen challenge. This concept has originated  in 1980s to explain T cell behavior following primary encounter with antigen (signal 1) in absence of co-stimulation (signal 2). Later, anergy concept was expanded to include T cell behavior following repetitive antigen encounter, similar to what today we would call T cell exhaustion.    

Generally speaking, anergic T cells are different from canonical thymic Foxp3+ Tregs. Anergic T cells do not express Foxp3 marker. While there are several surface and transcription factors that could "identify" anergic T cells, classical test for anergic T cells is to run several functional cytokine secretion assay and if memery/effector T cells do not produce cytokines, especially IL-2, and do not express Foxp3, you can call it anergic T cells. It is primitive but its all we have right now.  

In the past scientists thought that anergic T cells were necessary to maintain peripheral tolerance against self-antigens. It was believed that anergic T cells would compete for antigen access with self-reactive naive T cells (recent thymic emigrants) and would not allow their activation. This model lost its appeal once Foxp3T cells were re-discovered and re-defined. So, presently, functional significance of anergic T cells is in a kind of limbo.

So, it was interesting to see new paper in Nature Immunology that revisited the role of anergic T cells. In this study the authors tried to make sense of anergic T cells by postulating that some portion of anergic T cells represent precursors for classical Foxp3+ T regs.

First, the authors showed that among Foxp3-negative T cells, FR4hiCD73hi markers define anergic T cells (by low IL-2 production) that develop following antigen encounter in absence of co-stimulation (for example, pregnant females harbor pregnancy-associated anergic T cells specific for antigen [2W1S] expressed by male fetus). Interestingly, majority of those Foxp3-negative anergic T cells express neuropilin-1 (Nrp-1), a marker for thymus Tregs.

Next, the authors showed that in functional assays, FR4hiCD73hi anergic T cells behave very similar to classical Foxp3T cells.

Furthermore, when polyclonal Foxp3-FR4hiCD73hi anergic T cells were transferred into lymphopenic host, anergic T cells gave rise to classical Foxp3T cells (compared to naive or effector T cells).

Importantly, if those newly formed Foxp3T cells [derived from anergic T cells] were selectively deleted it led to systemic autoimmune disease, implying functional role for such daughter Foxp3T cells.

Finally, the authors showed that new Foxp3T cells formed from anergic T cells could prevent arthritis development when co-transferred with cartilage antigen-specific KRN T cells (that themselves do not become anergic or develop into Foxp3T cells).  

In summary, this study showed that some anergic T cells (especially Nrp1+ subpopulation) could give rise to peripheral Foxp3T cells. However, not all T cells can produce anergic T cell that could serve as a precursors for Foxp3T cells (for example KRN T cells or 5C.C7 CD4 T cells). It remains seen what role, if any, anergic T cells play in un-manipulated host. So far we lack tools to selectively deplete anergic T cells in un-manipulated host to test their real-world biological significance. Also, since anergic T cells resemble thymic Foxp3T cells in Npr1 expression, it will be interesting to found out whether anergy induction is a part of thymic Foxp3T cell development program, in general.

David Usharauli

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