Memory-like CD8+ and CD4+ T cells cooperate to break peripheral tolerance under lymphopenic conditions.
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 lymphopenia-driven proliferation and differentiation of potentially autoreactive CD8(+) T cells into memory-like cells is not sufficient to induce self-reactivity 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 memory-like 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.
Le Saout
Cecile
C
Institut de Génétique Moléculaire de Montpellier Unité Mixte de Recherche 5535, Centre National de la Recherche Scientifique, Université de Montpellier 1 and 2, 34293 Montpellier, Cedex 5, France.
Mennechet
Sandie
S
Taylor
Naomi
N
Hernandez
Javier
J
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology; D000939:Epitopes / Q000276:immunology; D006706:Homeostasis / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000276:immunology / Q000473:pathology
D000939:Epitopes