Tregs new motto: united we stand

Few days ago journal Nature has published thought-provoking study dealing with fundamental aspect of immune regulation by Foxp3⁺ Treg cells. 

Tregs are a major players within immune system but Tregs-mediated "negative" regulation of antigen-specific immune response has a fundamental problem at the theoretical, mechanistic level. No major, widely accepted immune theories such as Burnet's clonal selection theory, 2-signal model, Janeway-Medzhitov's PAMP model, or Matzinger's Danger theory could satisfactorily explain the role of Tregs within immune system. 

Actually, all these major immune theories excludes or simply prohibit the existence of any antigen-specific T cells that are of inhibitory nature. Antigen cannot be the basis of inhibition, according to these models, because T cell has no way of "knowing" the difference between self or nonself antigens. Moreover, at the innate immune system level, simply eliminating "irritants" that caused initiation of immune response in first place would automatically return immune system into quiet state without need of any negative regulation.

So why Tregs exist and how they regulate immune response? So this new paper tried to unlock the first door for this theoretical labyrinth. The authors showed that fraction of Tregs within lymph nodes are constantly active and constantly inhibiting proto-effector T cells. This suggests that Tregs function is more complex that typically assumed "off"/"on" model.

Initially, the authors led by Ron Germain at NIH, showed that lymph nodes contains functionally active Tregs clusters responding to local IL-2 in real time (phospho-STAT5).

Interestingly, the authors found no difference between active Treg clusters in wild-type and germ-free mice, suggesting that commensal bacteria derived non-self antigens were not responsible for Treg cluster formation (i.e. clusters were formed in response to self-antigens).

Next, the authors showed that when TCR signaling was interrupted in Tregs, these Treg clusters became small or disbanded.

Actual quantification of active, pSTAT5⁺ Tregs revealed both Treg cluster number and density of T regs within pSTAT5⁺ clusters were reduced in absence of TCR signaling, implying active role of antigen recognition for Treg cluster formation. Interestingly, total number of pSTAT5⁺ Tregs was not affected in absence of TCR signalling suggesting wider availability of free IL-2 secreted by proto-effector T cells in absence of suppressive Treg clusters (this could be compensatory increase in functionally impotent single Tregs).

This conclusion was supported by the fact that when IL-2 was blocked by anti-IL-2 antibody (that indirectly would have "inactivated" Tregs within clusters), there was an increase in IL-2 production by proto-effector CD4 T cells.

Finally, using more refined antigen-specific adoptive transfer experiment, the authors showed that when proto-effector CD4 T cells lacked IL-2 (and hence could not signal Tregs in clusters, these IL-2-deficient proto-effector CD4 T cells were able to form long-lasting interaction with dendritic cells, potentially increasing their chance for effector differentiation.     

In summary, this study suggests that Tregs are constantly scanning, responding and provide feedback to self-reactive proto-effector T cells in "steady state" within specialized "suppressor" clusters. But what happens to clusters during typical immune response?

In general the model proposed here is more like a network and I clearly see its basic similarity with Niels Jerne's Network model, a theory that was very popular during 80s but later was abandoned. Who knows, may be this paper is a new beginning for Network theory.

For Treg fans, Nature also published another, less impressive study from Rudensky's lab where the authors explored the role epigenetic modification of Foxp3 intronic enhancer, CNS3, in Treg TCR  repertoire variability and its role in preventing autoimmune inflammation.

David Usharauli