Memory-like CD8⁺and CD4⁺T cells cooperate to break peripheral tolerance under lymphopenic conditions

Abstract

The onset of autoimmunity in experimental rodent models and patients frequently correlates with a lymphopenic state. In this condition, the immune system has evolved compensatory homeostatic mechanisms that induce quiescent naive T cells to proliferate and differentiate into memory-like lymphocytes even in the apparent absence of antigenic stimulation. Because memory T cells have less stringent requirements for activation than naive cells, we hypothesized that autoreactive T cells that arrive to secondary lymphoid organs in a lymphopenic environment could differentiate and bypass the mechanisms of peripheral tolerance such as those mediated by self-antigen cross-presentation. Here, we show that lymphopeniadriven proliferation and differentiation of potentially autoreactive CD8 ؉ T cells into memory-like cells is not sufficient to induce selfreactivity against a pancreatic antigen. Induction of an organ-specific autoimmunity required antigen-specific CD4 ؉ T cell help. Notably, we found that this function could be accomplished by memory-like CD4 ؉ T cells generated in vivo through lymphopenia-induced proliferation. These helper cells promoted the further differentiation of memorylike CD8 ؉ T cells into effectors in response to antigen cross-presentation, resulting in their migration to the tissue of antigen expression where autoimmunity ensued. Thus, the cooperation of self-reactive memory-like CD4 ؉ and CD8 ؉ T cells under lymphopenic conditions overcomes cross-tolerance resulting in autoimmunity.autoimmunity ͉ T cell help ͉ T cell homeostasis

NK Cells Delay Allograft Rejection in Lymphopenic Hosts by Downregulating the Homeostatic Proliferation of CD8+ T Cells

“…Bar graphs are mean 6 SEM. lymphopenic hosts can cause autoimmunity (16,17), precipitate allograft rejection, and prevent tolerance induction (18)(19)(20)(21)(22). In these situations, concomitant NK and T cell depletion is detrimental to allograft survival as shown in our experiments.…”

“…A characteristic feature of homeostatic proliferation is the rapid generation of functional memory T cells from naive lymphocytes in the absence of cognate antigenic stimulation (8)(9)(10)(11)(12). Although beneficial to the host by providing immunity against infections and tumors (13-15), homeostatically generated memory T cells can cause autoimmunity (16,17) and, in the setting of organ transplantation, precipitate allograft rejection and resist tolerance induction (18)(19)(20)(21)(22). Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is essential for avoiding the unwanted consequences of lymphodepletion.…”

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

“…However, it is not known whether the expansion of potentially autoreactive T cells is itself sufficient to induce autoimmunity under lymphopenic conditions or whether other mechanisms are also required. (76,77). Tregs play an important role in suppressing preexisting autoreactive T cells and also control the LIP of other T cell subsets to prevent the generation of autoreactive T cell clones (78,79).…”

Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts

“…22 Recent studies have also shown a critical role for CD4 ϩ cells in breaking immune tolerance during lymphopenia, and it is possible that the lack of CD4 ϩ cells in the Rag1 Ϫ/Ϫ hosts limited the capacity to generate effective antitumor immunity. 42 Thus, profoundly lymphopenic hosts have diminished immune surveillance and an inability to generate determinant spreading during the evolution of antitumor immune responses. Furthermore, whereas the lymphopenic Rag1 Ϫ/Ϫ environment supported increased proliferation of adoptively transferred pmel-1 cells compared with cells transferred into lymphoreplete hosts, the highly proliferated cells showed diminished antigen-specific IFN-␥ production on a per-cell basis, compared with those transferred into lymphoreplete hosts ( Figure 5).…”