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Summary: CD4+ regulatory T cells (Treg) expressing the forkhead box protein 3 (FOXP3) transcription factor (Tregs) are instrumental for the prevention of autoimmune diseases. There is increasing evidence that the human T regulatory population is highly heterogeneous in phenotype and function. Numerous studies conducted in human autoimmune diseases have shown that Treg cells are impaired either in their suppressive function, in number, or both. However, the contribution of the FOXP3+ Treg subpopulations to the development of autoimmunity has not been delineated in detail. Rare genetic disorders that involve deficits in Treg function can be studied to develop a global idea of the impact of partial or complete deficiency in a specific molecular mechanism involved in Treg function. In patients with reduced Treg numbers (but no functional deficiency), the expansion of autologous Treg cells could be a suitable therapeutic approach: either infusion of in‐vitro autologous expanded cells, infusion of interleukin (IL)‐2/anti‐IL‐2 complex, or both. Treg biology‐based therapies may not be suitable in patients with deficits of Treg function, unless their deficit can be corrected in vivo/in vitro. Finally, it is critical to consider the appropriate stage of autoimmune diseases at which administration of Treg cellular therapy can be most effective. We discuss conflicting data regarding whether Treg cells are more effectual at preventing the initiation of autoimmunity, ameliorating disease progression or curing autoimmunity itself. [ABSTRACT FROM AUTHOR]

Granulomatous lymphomatosis is an Epstein-Barr virus ( EBV)-driven B cell proliferation associated with an exuberant CD4+ T cell reaction with usually histopathological pictures of angiocentrism. So far, the characteristics of CD4+ T cells in granulomatous lymphomatosis and the mechanism leading to their expansion remain poorly explored. We report a 56-year-old female with a past history of cold agglutinin disease, which was successfully treated with 4 weekly infusions of rituximab. She presented one year later with features of granulomatous lymphomatosis that resulted in severe lung and bone marrow infiltration. We provide evidence that CD4+ T cell expansion was oligoclonal, involved anergic cells and did not result from an EBV-driven stimulation. Rather, it resulted possibly from a high production of interleukin-10 by immunoblastic EBV-positive B cells. The outcome was remarkably favourable with rituximab and steroids. Our results suggest that an EBV-driven B cell proliferation should be investigated in patients presenting with a CD4+ T cells alveolitis or other systemic manifestations resulting from a CD4+ T cell expansion. These features should prompt to introduce an immunosuppressive therapy including steroids and rituximab. Our results deserve further investigations to confirm our pathophysiological hypotheses in CD4+ T cell expansions associated with EBV-driven B cell proliferations and to assess whether granulomatous lymphomatosis could result from comparable mechanisms. [ABSTRACT FROM AUTHOR]

Anti-leucocyte function-associated antigen-1 (LFA-1) antibodies can provide either stimulatory or inhibitory signals to T cells, depending on the epitope they recognize, type and stage of activation of the T cells, and nature of the activation stimulus. Because of the low affinity of interaction between the T-cell receptor (TcR) and the antigen/major histocompatibitity complex (MHC), it was proposed that the LFA-1 molecule strengthens the adhesion between the interacting cells, thus contributing in an additive manner to TcR-specific interactions. To check if high-avidity, TcR-specific interactions still require the accessory function of the adhesion molecule, we studied the effect of anti-LFA-1 antibodies on T-cell triggering mediated through chimeric receptors composed of an Fv of an antibody and a constant region of the TcR. Such chimeric TcR (cTcR) confer on T cells antibodytype specificity and affinity. We made use of transfected T-cell hybridomas expressing various amounts of either one cTcR chain (composed of VH linked to Cβ) or double-chain cTcR (VHCβ+VLCα). When such transfectants were stimulated with hapten-modified cells, anti-LFA-1 antibodies inhibited activation predominantly mediated through cTcR composed of a single chimeric chain and did not inhibit stimulation of the double-chain transfectants. Moreover, these anti-LFA-1 antibodies blocked antigen-specific T-cell activation regardless of whether the stimulus was adhesion dependent or not, such as in the case of stimulation by immobilized hapten-protein conjugates. These studies show that the 'off-signal' provided by anti-LFA-1 antibodies is adhesion independent and affects mainly low-avidity TcR-antigen interactions. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) transplantation, whatever its conditions, is associated with an increased risk of infections and tumoral complications, because of a delayed immune reconstitution. T-cell regeneration has been mostly investigated and appears to come more from graft and/or host mature T-cells, rather than from the differentiation/maturation of reinfused progenitors. In allogeneic setting, the immune defect is enhanced by the immune host/donor conflict and the use of prophylactic or curative immunosuppressive therapy. The tools used for studying post-transplant immunity are the following: immunophenotyping (kinetics and alterations of lymphocyte subset reconstitution), functional studies of T cell proliferation, cytokine production, cytotoxicity and signal transduction, as well as studies of T cell repertoire diversity. The CD4/CD8 cell immunophenotyping might be enough for routine clinical evaluation, allowing an adapted prophylaxis of opportunistic infections in those immune-suppressed patients, while functional assays might be useful to evaluate the persistence overtime of defects in immune reconstitution. These overall assays are useful both for basic and clinical research and allow better understanding in the mechanisms for T cell regeneration in the diverse types of HSC transplants performed nowadays particularly after graft of purified HSC where immune reconstitution remains a key question. [ABSTRACT FROM AUTHOR]

Our objective was to measure the relative proportions of messenger RNAs coding for soluble and membrane-bound Fas in peripheral blood mononuclear cells (PBMCs) and to quantify lymphocyte apoptosis in vitro in systemic lupus erythematosus (SLE). A RT-PCR (soluble/membrane Fas mRNA) ratio was calculated in 16 SLE, 11 RA and 16 healthy subjects’ PBMCs. Apoptosis was quantitated in vitro using nick-end labeling and flow-cytometry analysis immediately and after overnight T cell activation. The mean soluble/membrane Fas ratio was 1.219±0.424 in the SLE group, significantly higher than in healthy subjects, 0.516±0.180 (P=0.0001). There was no significant difference between inactive and active SLE groups whereas Fas ratio was higher in SLE patients with nephritis (1.460±0.365) compared to those without nephritis (1.031±0.380) (P=0.039). Mean soluble/membrane Fas ratio in RA patients (0.975±0.37) was higher than in healthy subjects (P=0.0003) and lower than lupus nephritis patients (P=0.015). A significantly higher proportion of mononuclear cells engaged apoptosis after T cell activation in active lupus patients, compared to control subjects. In comparison with healthy subjects, Fas alternative splicing was skewed toward the soluble form of Fas in SLE and RA. Apoptosis after T cell activation in vitro was increased in active SLE patients. [ABSTRACT FROM AUTHOR]