Dysregulation of T Lymphocyte Proliferative Responses in Autoimmunity

Abstract

T cells are critically dependent on cellular proliferation in order to carry out their effector functions. Autoimmune strains are commonly thought to have uncontrolled T cell proliferation; however, in the murine model of autoimmune diabetes, hypo-proliferation of T cells leading to defective AICD was previously uncovered. We now determine whether lupus prone murine strains are similarly hyporesponsive. Upon extensive characterization of T lymphocyte activation, we have observed a common feature of CD4 T cell activation shared among three autoimmune strains–NOD, MRL, and NZBxNZW F1s. When stimulated with a polyclonal mitogen, CD4 T cells demonstrate arrested cell division and diminished dose responsiveness as compared to the non-autoimmune strain C57BL/6, a phenotype we further traced to a reliance on B cell mediated costimulation, which underscores the success of B cell directed immune therapies in preventing T cell mediated tissue injury. In turn, the diminished proliferative capacity of these CD4 T cells lead to a decreased, but activation appropriate, susceptibility to activation induced cell death. A similar decrement in stimulation response was observed in the CD8 compartment of NOD mice; NOD CD8 T cells were distinguished from lupus prone strains by a diminished dose-responsiveness to anti-CD3 mediated stimulation. This distinction may explain the differential pathogenetic pathways activated in diabetes and lupus prone murine strains.

Healthy Donor Polyclonal IgMs Diminish B-Lymphocyte Autoreactivity, Enhance Regulatory T-Cell Generation, and Reverse Type 1 Diabetes in NOD Mice

“…These studies continue to point to the important role of autoreactive T cells and their collusion with islet-reactive B lymphocytes. The essential contribution of this interaction has been born out repeatedly in animal studies (5–8). More importantly, the presence of two anti-islet antibodies, which are produced by islet-reactive B lymphocytes, now is defined as a diagnosis of stage 1 T1D (9).…”

Regulation of B lymphocyte responses to Toll‐like receptor ligand binding during diabetes prevention in non‐obese diabetic (NOD) mice

“…Although the role of B lymphocytes in promoting autoreactive T cell activation is well known, it remains unclear how a soluble antigen such as insulin, which normally would induce a weak response, is able to promote robust immunity, class switching, and tissue destruction. It is clear in the murine model of T1D that insulin is the primary antigen upon which disease relies, and insulin‐reactive B cells are efficient drivers of rapid disease onset .…”

“…3,4 Although complete B cell depletion remains undesirable due to the risk of side effects, more targeted strategies to selectively deplete autoreactive B cells or induce B cell-mediated regulation remain highly attractive for clinical application. 5 Although the role of B lymphocytes in promoting autoreactive T cell activation is well known, [6][7][8][9][10][11] it remains unclear how a soluble antigen such as insulin, which normally would induce a weak response, is able to promote robust immunity, class switching, and tissue destruction. It is clear in the murine model of T1D that insulin is the primary antigen upon which disease relies, and insulin-reactive B cells are efficient drivers of rapid disease onset.…”