Engagement of antigen-specific T cell receptors (TCRs) is a prerequisite for T cell activation. Acquisition of appropriate effector T cell function requires the participation of multiple signals from the T cell microenvironment. Trying to understand how these signals integrate to achieve specific functional outcomes while maintaining tolerance to self is a major challenge in lymphocyte biology. Several recent publications have provided important insights into how dysregulation of T cell signalling and the development of autoreactivity can result if the branching and integration of signalling pathways are perturbed. We discuss how these findings highlight the importance of spatial segregation of individual signalling components as a way of regulating T cell responsiveness and immune tolerance.

The survival of long-lived plasma cells, which produce most serum immunoglobulin, is central to humoral immunity. We found here that the inhibitory Fc receptor FcgammaRIIb was expressed on plasma cells and controlled their persistence in the bone marrow. Crosslinking FcgammaRIIb induced apoptosis of plasma cells, which we propose contributes to the control of their homeostasis and suggests a method for therapeutic deletion. Plasma cells from mice prone to systemic lupus erythematosus did not express FcgammaRIIb and were protected from apoptosis. Human plasmablasts expressed FcgammaRIIb and were killed by crosslinking, as were FcgammaRIIb-expressing myeloma cells. Our results suggest that FcgammaRIIb controls bone marrow plasma cell persistence and that defects in it may contribute to autoantibody production.

The cytoplasmic phosphatase PTPN22 (protein tyrosine phosphatase non-receptor type 22) plays a key role in regulating lymphocyte homeostasis, which ensures that the total number of lymphocytes in the periphery is kept more or less constant. Mutations in PTPN22 confer an increased risk of developing autoimmune diseases. The precise function of PTPN22 and how mutations contribute to autoimmunity is controversial. Loss of function mutations in PTPN22 are associated with increased numbers of effector T cells and autoreactive B cells in humans and mice; however, the complete absence of PTPN22 in mice does not result in spontaneous autoimmunity.We found that PTPN22 was a key regulator of regulatory T cell (Treg) function by fine-tuning the functions of the T cell receptor (TCR) and integrins. PTPN22 -/-Tregs were more potent suppressors than were wild-type Tregs, and they suppressed the activity of PTPN22 -/-effector T cells and maintained tolerance. Mechanistically, PTPN22 -/-Tregs showed increased IL-10 production and elevated LFA-1 mediated adhesion, processes critical for Treg function. This previously undiscovered role of PTPN22 in regulating integrin signaling and Treg function could prove to be a useful therapeutic target for manipulating Treg function in human disease. ‡

No abstract