Accelerated Memory Cell Homeostasis during T Cell Depletion and Approaches to Overcome It

Abstract

Partial T cell depletion is used in solid organ transplantation as a valuable strategy of peritransplant induction immunosuppression. Using a murine cardiac allograft model, we recently demonstrated that this led to lymphopenia-induced (homeostatic) proliferation among the residual nondepleted lymphocytes. Rather than promoting tolerance, peritransplant T cell-depleting Abs actually resulted in resistance to tolerance induction by costimulatory blockade. In this study we show that memory T cells predominate shortly after subtotal lymphodepletion due to two distinct mechanisms: relative resistance to depletion and enhanced homeostatic proliferation. In contrast, regulatory cells (CD4+CD25+Foxp3+) are depleted as efficiently as nonregulatory cells and exhibit reduced homeostatic expansion compared with memory cells. The resistance to tolerance induction seen with subtotal T cell depletion can be overcome in two different ways: first, by the adoptive transfer of additional unprimed regulatory cells at the time of transplant, and second, by the adjunctive use of nondepleting anti-CD4 and anti-CD8 mAbs, which effectively block homeostatic expansion. We conclude that the resistance to tolerance induction seen after subtotal lymphocyte depletion can be attributed to alterations in the balance of naive, memory, and regulatory T cells. These data have clinically relevant implications related to the development of novel strategies to overcome resistance to tolerance.

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

“…17,18 We propose that antigen stimulation during homeostatic proliferation will selectively expand antigen specific lymphocytes, which has been well characterized by others in adoptive transfer mouse models. 15,16 We detected the kinetic changes of those effector-memory T cells and found that the proportion of CD44 high T cells increased in accordance with the recovery of cell numbers. However, the enhancement of effector-memorylike T cells is not sufficient for breaking immunotolerance to tumor weak antigens.…”

“…and acquire many of the surface markers of effector-memory T cells (e.g., CD44 high and CD62L low ). 15,16 Those divided effector-memory T cells possess similar functions of natural memory T cells and are reliable for priming when exposed to antigens. 17,18 We propose that antigen stimulation during homeostatic proliferation will selectively expand antigen specific lymphocytes, which has been well characterized by others in adoptive transfer mouse models.…”

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

“…Therefore, the assessment of pretransplant donor-specific cellular alloreactivity seems to be an important tool to discriminate those patients at risk for developing acute rejection after transplantation. 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).…”

Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection

“…A recent report (61) suggests that regulatory T cells can control homeostatic proliferation. The notion of combining anti-T cell treatment to deplete the bulk of alloreactive T cells with regulatory T cells to control the remaining T cell population has already been suggested and experimentally demonstrated to be effective as an adjunct to tolerance induction by Turka and colleagues (51). If this strategy is used, then careful use of regulatory T cells after T cell depletion may serve the dual purpose of controlling the rejection process by the remaining T cells as well as preventing their excessive homeostatic proliferation and acquisition of memory phenotype and function, at the same time maintaining host defense against external pathogens.…”