Response to self antigen imprints regulatory memory in tissues

Abstract

Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathologic autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration1. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression2. In the practice of antigen-specific immunotherapy (antigen-SIT), allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure3. Although these findings suggest that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (Treg cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity. After resolution of the inflammatory response, activated Treg cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, Treg cells function to confer ‘regulatory memory’ to the target tissue. These findings provide a framework for understanding how Treg cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity.

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

“…Much, albeit not all, of the dampened signaling in Treg cells could be ascribed to their higher proportion of CD44 hi effector/ memory cells (28)(29)(30). Signaling cascades are less readily activated via the TCR in such cells (27), and this distinction also applies to Treg cells.…”

“…Responses to TCR engagement are known to be less intense in memory than in naïve T cells (27), and this could be an important confounder, as a significant fraction of Treg cells have a memory phenotype (28)(29)(30). We used the expression of CD44 and CD62L molecules to distinguish between naïve and memory phenotypes during the response to CD3/CD28 cross-linking.…”

In Vivo Environment Necessary to Support Transplanted Donor Mouse T Regulatory Cells

“…Indeed, T regs are detected within tolerant grafts (3,5,50), indicating alloreactive T regs could be recruited to or even retained at sites of alloantigen expression and actively participate in tolerance induction or maintenance. Rosenblum et al (52) found self-Ag expression in skin resulted in T regs that are activated, more potent suppressors and maintained within skin, which offered subsequent protection when self-Ag is re-expressed. Joffre et al (25) demonstrated that T regs expanded in vitro with directly or indirectly presented donor antigens prevents both acute and chronic rejection.…”

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

“…The expansion peaks around the first month after HSCT and appears to contract by activation-induced cell death (AICD). It still remains unclear whether some part of graft-derived Treg would survive or not as functionallymemory suppressor cells for a long time after HSCT [26].…”