CD4+ Regulatory T Cells Are Spared from Deletion by Antilymphocyte Serum, a Polyclonal Anti-T Cell Antibody

Abstract

Broad T cell depletion has been used as an integral part of treatment in transplantation and autoimmune diseases. Following depletion, residual T cells undergo homeostatic proliferation and convert to memory-like T cells. In this study, we investigated the effect of T cell depletion by antilymphocyte serum (ALS), a polyclonal anti-T cell Ab, on CD4+ regulatory T cells. After ALS treatment, CD4+CD25+ T cells underwent proliferation and expressed a memory T cell marker, CD44. One week after ALS treatment, both CD25+ and CD25− T cells exhibited increased suppression of alloresponses in vitro, which waned thereafter to the levels mediated by naive CD25+ and CD25− T cells. By real-time PCR analyses, ALS treatment of CD4-deficient mice adoptively transferred with Thy1.2+CD4+CD25+Foxp3+ and Thy1.1+CD4+CD25−Foxp3− T cells resulted in the appearance of Thy1.2+CD4+CD25−Foxp3+ and Thy1.1+CD4+CD25+Foxp3+ T cells, suggesting the conversion between CD25+ and CD25− T cells. Naive CD25+ T cells expressed a higher level of intracellular Bcl-xL than CD25− T cells. Up-regulation of the Bcl-xL molecule during ALS-induced homeostatic expansion further promoted survival of CD25+ and, to a lessor degree, CD25− cells. These results indicate that CD25+ T cells are spared from ALS-mediated deletion, with some CD25+ T cells converting to CD25− T cells, and continue to exhibit regulatory activity. The concomitant presence of T cell deletion and continuous regulatory T cell activity may underlie the therapeutic effect of ALS, particularly in treatment of autoimmune diseases.

Anti-TCR Antibody Treatment Activates a Novel Population of Nonintestinal CD8αα+TCRαβ+ Regulatory T Cells and Prevents Experimental Autoimmune Encephalomyelitis

“…Interestingly, polyclonal anti-lymphocyte serum has also been shown to spare the CD4 ϩ CD25 ϩ Tregs from deletion although it deletes most of the other lymphocytes. At least 2 wk after anti-lymphocyte serum treatment it appeared that the residual CD4 ϩ CD25 ϩ Tregs showed a much stronger in vitro suppressive activity (48). Although the mechanisms of the above polyclonal anti-lymphocyte sera appear complex, our data collectively suggest that anti-TCR Ab-mediated activation of the CD8␣␣ Tregs in vivo provides an important pathway for generating an effective regulatory response with potential clinical implications for the therapy of autoimmune diseases and transplant rejections.…”

Achieving Donor-Specific Hyporesponsiveness Is Associated with FOXP3+ Regulatory T Cell Recruitment in Human Renal Allograft Infiltrates

“…Recently, it has been shown that more than just acting as a T cell depletion agent, rATG is able to induce a significant increase of Treg in vitro (25), although it has been suggested that Tregs are quite sensitive to elimination by depleting Abs (45). However, it has also pointed out that the relative resistance of Tregs to apoptosis can promote tolerance through preferential depletion of Teffector cells (46,47). In contrast, optimal concentrations of rATG for in vitro generation of Tregs appear to occur at significantly lower levels than those achieved in serum after treatment with standard rATG doses in vivo (42,48).…”

CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia

“…2b). The relative resistance of this T cell subset to various conditioning regimes (29,47), as well as depletion by HIV infection (48,49), has been reported previously.…”