Search

Regulatory T lymphocytes (Treg) are fundamental for immune homeostasis since they contribute to the induction of peripheral tolerance to autologous antigens and regulate effector immune responses. Treg subsets are present within both the CD4+and the CD8(+) T cell compartments. Considering the CD8(+) Treg, in the last decades several subpopulations, provided with different phenotypes and mechanisms of action, have been characterized. This review is an attempt of integrating in an organic scenario the different CD8(+) Treg subpopulations. Moreover, it summarizes the findings so far achieved on the existence of CD8(+) Treg alterations in autoimmune diseases.

The mechanism underlying the generation of T and B autoreactive clones in autoimmune diseases is still unknown. Among genetic factors implicated in autoimmunity, Autoimmune Regulator gene (AIRE) is one of the candidates to better understand the complex scenario of autoimmune manifestations. AIRE mutations are responsible for the development of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) with monogenic autosomal recessive inheritance; it has been shown that AIRE regulates the negative selection of autoreactive T cells clones, driving the transcription of tissue-specific antigens in thymic epithelial cells. In various autoimmune manifestations correlated or not to APECED, AIRE variants act in a semidominant manner, leading to a reduction in AIRE protein amount per cell, and consequently to a marked decrease in ectopic proteins expression in the thymus. The co-occurrence of autoimmune diseases in the same individual has prompted several studies aimed to recognize shared patho-physiological mechanisms; in this scenario small reductions in function could explain the predisposition to autoimmunity in AIRE-heterozygous carriers of missense mutations; further studies to investigate whether the AIRE gene is involved in determining these autoimmune manifestations should be carried out.

The CD8+ T suppressor lymphocytes identified in humans belong to three different subpopulations. All of them inhibit the proliferation of antigen-specific T cells. The type 1 and type 2 of CD8+ T suppressor cells are characterized by the CD8+CD28- phenotype, while no detailed data are available at the moment on the phenotype of the type 3 of CD8+ T suppressor cells. The type 1 of CD8+ suppressor T lymphocytes acts by inducing alteration of expression of co-stimulatory molecules on dendritic cells. A cell-to-cell contact is required to mediate this effect. The type 2 of CD8+ T suppressor cells induces inhibition via cytokine secretion (IFNgamma, IL6) and do not need to interact directly with antigen presenting cells. The type 3 of CD8+ T suppressor cells mediates its function through the secretion of IL10. The complexity and multiplicity of CD8+ T suppressor cell subsets suggests that these cells may have an important role in the regulation of the immune homeostasis, acting together with the CD4+ T regulatory cell subpopulations. The specificity of the functions of each of these suppressor/regulatory subsets in the immune network requires to be clarified to better understand the immune system, its functions and the possibilities to modulate its activities in the course of immune-mediated diseases.

Objective: To demonstrate the involvement of T lymphocytes reactive to autoantigens in the pathogenesis of autoimmune diseases and to analyse their clinical relevance., Methods: The frequency of T cell clones reactive to double strand DNA (dsDNA), Nucleohistone (NH) complex and Dnase I was calculated for the peripheral blood mononuclear cells (PBMC) of 15 SLE patients and 9 healthy subjects by proliferation assay., Results: DsDNA- and NH-specific T cell clones were found in the majority of the patients analysed (frequency ranging from 2 to 50 clones/10(7) PBMC), while their absence or very low frequency (2 clones/10(7) PBMC) was observed in the control PBMC. Their frequency significantly correlated with decreased serum concentrations of C3 and C4 and with the systemic lupus erythematosus disease activity index (P = 0.03). A very low frequency of Dnase I-reactive T cell clones was observed in both SLE and healthy subjects., Conclusion: Our results suggest that dsDNA- and NH-reactive T lymphocytes may be involved in the pathogenesis of SLE and that their quantification in the peripheral blood of patients could be a useful tool to follow the clinical course of the disease.

Abstract: Mutations in the autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). Systemic sclerosis (SSc) is a non-organ-specific autoimmune disease mainly characterized by cutaneous involvement, that is frequently associated with other autoimmune manifestations common to APECED. Nineteen SSc patients, 22 patients affected by SSc associated with autoimmune thyroiditis, and 100 healthy controls were analyzed. We identified 11 AIRE gene variants, one of which has never previously been described. Intronic polymorphism G11107A was significantly correlated to SSc/thyroiditis. Data show that variants of the AIRE gene might be correlated to different clinical manifestations in SSc patients. [Copyright &y& Elsevier]