CD4+CD25HIGH regulatory T cell homeostasis and function in healthy individuals and patients with multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). T cells specific for components of the myelin sheath are considered to be initial effectors in the autoimmune reactions observed in MS. CD4+CD25high regulatory T cells play an important role as suppressors of T cell mediated immune reactions. The suppressive capacity of Tregs is reduced in patients with relapsing-remitting MS (RR-MS). In contrast, patients with a secondary progressive disease course (SP-MS) show a normal Treg function. It remains unknown why the Treg function is aberrant in RR- and SP-MS patients. The functional characteristics of Tregs in MS patients were further evaluated in this study. In this respect the suppressive capacity of conventional Tregs and the recently described naive Tregs were evaluated in MS patients. In addition, parameters of T cell homeostasis (sjTRECs, CD31 expression and T cell receptor BV usage) were measured on Tregs to gain more insight in the dynamics of this T cell population in HC and MS patients. The frequency of functional naive Tregs and memory Tregs were both reduced in RR-MS patients as compared to HC. The number of sjTRECs was lower in naive and memory Tregs of RR-MS patients. Moreover, memory Tregs show a decreased expression of CD31. In addition, the TCR BV gene usage of these cells is altered. These results provide indications of a disturbed Treg homeostasis in MS patients. The suppressive capacity of nnTregs and memory Tregs was reduced in RR-MS patients. Interestingly, memory Tregs of RR-MS patients with a long disease duration and SP-MS patients showed a normal suppressive capacity, comparable with healthy individuals. In contrast, the suppressive capacity of nnTregs remained reduced in these patients. Indications are provided that the functional memory Tregs are induced from conventional T cells in the periphery of RR-MS patients. The Treg suppressive capacity towards myelin specific responses was also evaluated. Tregs of healthy individuals were able to suppress responses towards myelin antigens. Adequate suppression of myelin reactive T cells may be importance as this population contains potentially pathogenic Th1 and Th17 cells. The results of this study could contribute to an enhanced insight into the role of Tregs in the pathogenesis of MS. Further research of the function and the processes which affect Treg homeostasis is needed before any attempts are made to manipulate these cells therapeutically.