CD4+ Foxp3+ regulatory T cell homing & homeostasis
CD4+Foxp3+ T cells (TR) are essential for maintaining self-tolerance, but their sites of action in vivo and homeostatic mechanisms are poorly defined. I examined homing receptor (HR) expression by TR in the steady state and determined whether altering TR distribution by removal of CCR4 impairs their ability to maintain tissue-specific tolerance. Additionally, I examined signals that alter TR HR expression and what impact this has on TR homeostasis.I found TR in all non-lymphoid tissues tested, particularly in skin, where they express a unique CCR4+CD103hi phenotype. TR expression of CCR4 and CD103 is induced by antigen-driven activation within sub-cutaneous lymph nodes, and accumulation of TR in skin and lung airways is impaired in the absence of CCR4 expression. Mice without CCR4 expression in TR develop inflammatory disease in skin and lungs, accompanied by lymphadenopathy and an increase in skin-tropic CD4 +Foxp3- T cells. Additionally, CCR4-ligand interactions mediate efficient homeostasis of TR. CCR4-deficient TR undergo faster homeostatic expansion than WT TR, but cannot sustain themselves during homeostatic maintenance. Together, these data highlight the importance of CCR4 expression by TR in meditating their localization. This is crucial for their activity within non-lymphoid tissues to protect against tissue-specific disease, as well as within lymphoid tissues to receive homeostatic signals.I also explored the contribution of signals mediated by Wiskott-Aldrich syndrome protein (WASp) to TR homeostasis. WASp is essential for optimal T cell activation and patients with WAS exhibited both immunodeficiency and autoimmunity. We investigated whether impaired TR function explained these paradoxical observations. WASp-deficient (WASp1- ) mice exhibited normal thymic TR generation, but the competitive fitness of peripheral TR was compromised. The percentage of Foxp3 + TR was reduced, and WASp-/- TR were outcompeted by WASp+ TR in vivo. These findings correlated with reduced expression of HR associated with self-antigen-driven TR activation and homing to inflamed tissue. Furthermore, WASp-/- TR were unable to control lymphocyte activation and autoimmune pathology in Foxp3-/- sf mice. Finally, WASp + TR exhibited a selective advantage in a WAS patient with a revertant mutation, indicating that altered TR fitness likely explains the autoimmune features in human WAS.
- Immunology