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. ‡

FcγRIIb is an inhibitory Fc receptor expressed on B cells and myeloid cells. It is important in controlling responses to infection, and reduced expression or function predisposes to autoimmunity. To determine if increased expression of FcγRIIb can modulate these processes, we created transgenic mice overexpressing FcγRIIb on B cells or macrophages. Overexpression of FcγRIIb on B cells reduced the immunoglobulin G component of T-dependent immune responses, led to early resolution of collagen-induced arthritis (CIA), and reduced spontaneous systemic lupus erythematosus (SLE). In contrast, overexpression on macrophages had no effect on immune responses, CIA, or SLE but increased mortality after Streptococcus pneumoniae infection. These results help define the role of FcγRIIb in immune responses, demonstrate the contrasting roles played by FcγRIIb on B cells and macrophages in the control of infection and autoimmunity, and emphasize the therapeutic potential for modulation of FcγRIIb expression on B cells in inflammatory and autoimmune disease.

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T cells must be tolerant of self-antigens to avoid autoimmunity, but responsive to foreign-antigens to provide protection against infection. We found that in both naive and effector T cells, the tyrosine phosphatase, Ptpn22 limits T cell receptor signaling by weak agonist and self-antigens, while not impeding responses to strong agonist antigens. T cells lacking Ptpn22 show enhanced conjugate formation with antigen presenting cells pulsed with weak peptides, leading to their activation and production of inflammatory cytokines. This effect is exacerbated under conditions of lymphopenia with the formation of potent memory T cells in the absence of Ptpn22. These data address how loss of function PTPN22 alleles can lead to expansion of effector/memory T cells and a predisposition to human autoimmunity.

Objective. Following the demonstration that the stress protein, BiP, prevented induction of collageninduced arthritis (CIA) in HLA-DRB*0101 ؉/؉ (HLA-DR1 ؉/؉ ) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA-DR1 ؉/؉ and DBA/1 mice.Methods. BiP was administered either subcutaneously or intravenously to DBA/1, HLA-DR1 ؉/؉ , or interleukin-4 (IL-4)-knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti-CII antibodies were measured by enzyme-linked immunosorbent assay. Disease progression was scored using a visual analog scale.Results. BiP was successful in suppressing estab-

Abstract:Integrins are transmembrane heterodimers that play a fundamental role in the migration of leukocytes to sites of infection or injury. Here, we provide evidence that the protein tyrosine phosphatase PTPN22 is a novel regulator of LFA-1 signaling in effector T-cells.PTPN22 co-localizes with its substrates at the leading edge of cells migrating on ICAM-1. Gene targeting, or expression of the autoimmune disease-associated PTPN22-R620W variant, results in hyper-phosphorylation of integrin signaling intermediates. Super-resolution imaging reveals that in the steady state PTPN22-R620 exists in large clusters that disaggregate upon LFA-1 stimulation, permitting increased association with its binding partners at the membrane. Failure to retain PTPN22-R620W molecules at the membrane leads to increased LFA-1 clustering and integrin-mediated cell adhesion. Our data define a novel mechanism for fine-tuning integrin signaling in T-cells, and a new paradigm of autoimmunity in man in which disease susceptibility is underpinned by inherited perturbations of integrin function.One Sentence Summary: PTPN22 is a negative regulator of integrin signaling and loss-offunction mutants increase cell adhesion.3