Homeostatic proliferation is a barrier to transplantation tolerance

Abstract

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells 1,2 . Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials [3][4][5][6] . But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation 7,8 , may induce acquisition of functional memory T cells 9-13 . Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.T cells undergo homeostatic proliferation when transferred into severe combined immunodeficiency (scid), recombination-activating gene-deficient or irradiated recipients7 ,8 . In many clinical transplantation protocols, T-cell depletion is less profound. We therefore asked whether residual nondepleted cells could undergo homeostatic proliferation. We treated mice with two doses (100 μg/dose) of depleting monoclonal antibodies directed at CD4 and CD8 (days 0 and 5). This induced 80-90% T-cell depletion, which was maintained for >10 d after the last dose (data not shown).

CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo

“…Therefore, a role for CD8 blockade in promoting expansion of tolerant regulatory cells, including Th2-type cells, by blocking CD8 + T cell function is plausible. In addition, a growing body of literature now shows that a reduction in total T cell number, either by the use of protocols that result in T cell depletion [85], or by the transfer of small numbers of T cells into immunodeficient hosts [86], or by genetically-induced lymphopenia [87], results in proliferation of both CD4 + and CD8 + T cells (T cell homeostatic proliferation). Although such homeostatic proliferation has not yet been described for regulatory CD4 + T cells, it is possible that depletion of CD8 + T cells by the CD8-specific mAb used in this model (data not shown) simply provides space into which regulatory, and other CD4 + T cells can expand.…”

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…It has long been observed that transfer of small numbers of T cells into lymphopenic hosts results in T-cell expansion, a process described as homeostatic proliferation [9][10][11][12][13][14][15][16]. As the T cells proliferate, they assume an Ag-experienced or memory phenotype, which is indicated by upregulation of CD44, Ly6C and CD122 (IL-2-IL-15Rβ) [12,15].…”

“…The proliferation of adoptively transferred Tcells in lymphopenic hosts can be reduced in a dose-dependent manner, either by increasing the total number of Ag-specific cells transfused or by co-transferring an 'irrelevant' population of Tcells [9,15,16,22]. Host CD8 + Tcells have a dominant role in modulating both donor CD8 + and CD4 + T-cell expansion in lymphopenic hosts [16].…”

The Innate Immune System in Allograft Rejection and Tolerance

“…More recently, Chalasani et al (45) used a "healed-in" model in which allograft recipients had an endogenous T cell compartment, eliminating the effect homeostatic proliferation has on tolerance induction (46). Cardiac allografts were allowed to heal for 70 days in splenectomized, alymphoplastic hosts, which have T cells but are devoid of secondary lymphoid organs, thus preventing naive T cell priming.…”