Regulation of Immunity
The acquisition and execution of CD4 effector function are tightly regulated and spatially compartmentalized. In the lymph node (LN), naïve CD4+ T cells acquire specialized functions by means of expression of distinct cytokines and acquire distinct homing properties. Therefore both the function and subsequent localization of effector cells appears to be pre-determined during differentiation in the LN. However, once CD4 effectors leave the lymph node their physical and functional fate is less well understood.
The location and inflammatory context in which effector T cells are reactivated at the infection site are likely to determine the success of a given immune response. Our research focuses on mechanisms of immune regulation at tissue sites of inflammation.
Our studies with the protozoa Leishmania major suggest that this centrally (LN) generated effector repertoire can be further edited at the infected tissue site. Cytokine production in the inflamed tissue can be modulated at a number of levels including chemokine-driven differential recruitment of effector cells, the provision of signals for effector cell function and suppression by regulatory T cells (Tregs). The concept that tissue resident pathogens may subvert the centrally generated cytokine repertoire has important therapeutic implications. Novel therapies that focus on manipulating the local infection site to encourage appropriate recruitment or activation of effectors may be particularly beneficial.
Regulatory T cells play important immuno-modulatory roles at sites of inflammation in both infection and autoimmunity. Nonetheless, their mode of suppression remains controversial and is likely to be context dependent and modified by the inflammatory milieu. We focus on the molecular consequences of Treg encounter for the CD4+ T cells and have identified important points of control for early IL-2 production and for Th differentiation and effector function. Regulatory T cells can readily be found at sites of inflammation in infectious and autoimmune settings. It is clear that their activity also needs to be regulated in order to enable protective immunity to proceed but that these mechanisms of control may exacerbate autoimmune pathology. We are interested in the functional fate of Tregs at sites of inflammation, particularly in the context of autoimmune diabetes.
- Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels. J Exp Med. 209, 1349-62. (2012 Jul 02).
- Cutting edge: Regulatory T cells selectively attenuate, not terminate, T cell signaling by disrupting NF-κB nuclear accumulation in CD4 T cells. J Immunol. 188, 947-51. (2012 Feb 01).
- Leishmania induces survival, proliferation and elevated cellular dNTP levels in human monocytes promoting acceleration of HIV co-infection. PLoS Pathog. 8, e1002635. (2012 Jan 01).