CD69 and mucosal tolerance

Soon after birth every one of us is colonized with multiple bacterial species that stay in our intestinal tract throughout the lifetime.  The gut microbiota participate in many vital processes – they support our digestion and metabolism as well as perform important instructive role for the immune system. Yet these commensal organisms express similar conserved molecular patterns as pathogens and are obviously capable to stimulate the innate arm of immunity. They are also equipped with considerable antigenic load (their biomass is many times bigger than pathogens’ biomass) that has to be the target of adaptive anticipatory receptors. However, in normal circumstances the microbiota presence is accommodated without any ill effects. Why they are not actively assaulted by the immune system? In all probability there is no single and easy answer to this question. How the immune system discriminates between commensal and pathogenic bacteria forms one of the most interesting puzzles faced by the immunology. Our body can use unrecognized strategies to ensure the tolerance at its intestinal compartments.

The link:

This publication is based on the original finding that CD69 (the marker of activated lymphocytes) is predominantly up-regulated by CD4 T cells located at mucosal surfaces. Authors provide evidences that CD69-positive cells appear to be in the state of immune impassiveness as they secrete only TGF-β1 – a cytokine involved in modulation of inflammatory reactions. Additionally, CD69 up-regulation on CD4 T cells is able to suppress the expression of stimulatory cytokines IFN-γ, TNF-α and IL-21. The functional role of CD69 expression is assessed with two experimental approaches – inducible colitis (by adoptive transfer of CD45RBhigh CD4 T cells into RAG / animals) and oral tolerance (by feeding and subsequent immunization with model antigen OVA). It is demonstrated that CD69 deficiency on CD4 T cells causes worse colitis outcome and lack of toleration to orally delivered antigen.

In spite of these intriguing data, I am most interested by one observation that has been left almost unexplored throughout the whole paper. Authors use OVA transgenic (with CD4 T cell compartment transgenic in over 90%) and OVA transgenic on RAG / background (having exclusively transgenic CD4 T cells) strains to show that the cognate activation of CD4 T lymphocytes is necessary to induce CD69 up-regulation. Surprisingly, it looks like the requirement for TCR signaling is not absolute and CD4 T cells from specific anatomical site – the colon – can become activated without TCR ligation (given that we assume that CD69 expression is really the reliable marker of CD4 T cell activation). Data indicate that CD69 expression on OVA transgenic CD4 T cells from the colonic lamina propria is refractory to any reduction even in the absence of OVA. Authors argue that type I IFN signaling is important in both up-regulation of CD69 and protectiveness mediated by CD69-positive cells. It cannot explain, however, why CD4 T cells from colon are so persistently activated without the cognate antigen because IFNAR-deficient mice display similar to wild type levels of CD69 expression (and thus activation) on CD4 T cells at all anatomical locations tested.

In the natural setting CD69 expression is relatively modest on lymphocytes from spleen and mesenteric lymph nodes but it reaches the highest level (approximately 50%) on cells from small intestine and colonic lamina propria. CD69 expression on CD4 T cells is also strictly dependent on the presence of bacterial microbiota which is a common feature of many other immune activities connected to the gastrointestinal tract. The colon is inhabited by greatest number of commensal bacteria than any other part of our body. The steady activation status of colonic CD4 T cells combined with the general modulatory behavior of CD69-positive lymphocytes provokes multiple questions. The most important I would ask is whether the presumed TCR-independent activation of CD4 T cells can be confirmed as the physiologically relevant process occurring in the gut. Can we identify receptors or molecules that convey these activation signals? May it be yet another mechanism accounting for intestinal microbiota tolerance?

Radulovic, K., Manta, C., Rossini, V., Holzmann, K., Kestler, H., Wegenka, U., Nakayama, T., & Niess, J. (2012). CD69 Regulates Type I IFN-Induced Tolerogenic Signals to Mucosal CD4 T Cells That Attenuate Their Colitogenic Potential The Journal of Immunology, 188 (4), 2001-2013 DOI: 10.4049/jimmunol.1100765

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