Differences in T regulatory cells between mouse strains frequently used in immunological research: Treg cell quantities and subpopulations in NOD, B6 and BALB/c mice

Abstract

Foxp3⁺ Regulatory T cells (Tregs) are essential for the maintenance of tolerance to self. Therefore, it is expected that lower numbers and/or less than optimal function could impact on the functioning of the immune system, and thereby contributing to the development of autoimmune diseases. In the present report, by comparing Tregs from most frequently used mouse strains in immunological research (C57BL/6 (B6), BALB/c and NOD), we provide evidence showing that the NOD mouse strain, highly predisposed to develop autoimmune responses, exhibit a generalized decreased in Tregs counts with enhanced proportions of CD44^hiCD62L^low Tregs when compared with BALB/c mice. No major differences were observed in Helios⁺ or Helios- Tregs between strains. The expression of CXCR3, CCR5 and CCR6 on Tregs from all strains showed minor proportions of CXCR3⁺ and CCR5⁺ cells in NOD Tregs. Naïve CD4⁺CD25- T cells from NOD mice also showed decreased capacity to induce in vitro iTregs when compared with B6 and BALB/c mice. Lower expression of molecules involved in Treg suppressor mechanisms such as CD25, LAP-1, CD39 and PD-1 was observed both in NOD iTregs and Tregs from lymph nodes of NOD mice. Moreover, in vitro assays showed that Tregs from NOD mice exhibited reduced ability to suppress proliferation of CD4⁺CD25- responder T cells when compared with B6 and BALB/c mice. Major differences were consistently observed between NOD and BALB/c mice, whereas no major differences were found for many of the analyzed parameters between the NOD and B6 mice, suggesting that highly and mildly autoimmune prone mouse strains may share some Tregs features. On the contrary, BALB/c Tregs were in major quantities, expressed higher levels of Foxp3 and exhibited more potent ability to inhibit effector T cell proliferation, data that could be related to its natural resistance to the induction of different experimental autoimmune conditions. Altogether our results demonstrate a generalized Treg cell dysfunction in NOD mice, a strain characterized by its high predisposition to develop spontaneous and induced autoimmune diseases.

Keywords: Chemokine receptors; NOD mice; Naïve and Central memory Tregs; iTregs; regulatory T cells.