Background/Purpose: We have shown that repeated immunization with antigen induces systemic lupus erythematosus (SLE) in the mice otherwise not prone to spontaneous autoimmune diseases. We found that overstimulation of CD4 T cells led to the development of autoantibody-inducing CD4 T (aiCD4 T) cell which had undergone de novo T cell receptor (TCR) revision, capable of inducing variety of autoantibodies and stimulating CD8 T cells, driving them to become cytotoxic T lymphocyte (CTL). These CTLs then matured through antigen cross-presentation in dendritic cell (DC), after which they caused tissue injury identical to SLE. We have proposed Self-Organized Criticality Theory, explaining that systemic autoimmunity would be an inevitable consequence of over-stimulating host’s immune system by repeated immunization with antigen to levels that surpass system’s self-organized criticality. Since the aiCD4 T cell appeared to be included in CD45RB^lo122^lo CD4 T cell subset, we here further dissected the phenotype of the aiCD4 T cell by pursuing this subset, and found that aiCD4 T cells include not only follicular helper T (Tfh) cell but also IL-21-producing CXCR5^–ICOS^hiPD-1^hi cell, and this subset seemed to be responsible for the induction of SLE.

Methods: BALB/c mice were repeatedly immunized with ovalbumin (OVA) and SLE was induced. CD45RB^hi or CD45RB^lo CD4 T cells in spleen of these mice were studied the expression of cell surface marker using flow cytomery. Splenic CD45RB^hi or CD45RB^lo CD4 T cells were also magnetically isolated and stimulated by anti-CD3 and anti-CD28 antibodies in vitro. After stimulation, IL-21 in culture supernatant were detected using ELISA. IL-21-producing CD4 T cell was also detected using flow cytomery.

Results: After repeated immunization with OVA, the CXCR5⁺PD-1^hi Tfh cell was significantly increased. A unique CXCR5^–PD-1^hi CD4 T cell subset was also increased in the OVA-immunized mice. These subsets were, however, absent in the CD45RB^hi subset. The expression of ICOS was equally high in both subsets as compared with conventional CXCR5^–PD-1^– CD4 T cells, however, the expression of Bcl-6 was lower in the CXCR5^–ICOS^hiPD-1^hi CD4 T cells as compared with Tfh cells. The amount of IL-21 produced from CD45RB^lo CD4 T cell of OVA-immunized mice was significantly high as compared with CD45RB^hi CD4 T cell of OVA-immunized mice or whole CD4 T cell of control mice. IL-21-producing CD4 T cell was also significantly increased within CD45RB^lo subset after repeated immunization with OVA. We also found that CXCR5^–PD-1^hi CD4 T cells produced much more IL-21 as compared with Tfh cells after repeated immunization with OVA.

Conclusion: The CXCR5^–ICOS^hiPD-1^hi CD4 T cells that produce IL-21 were significantly increased in addition to Tfh cells in the mice repeatedly immunized with OVA. This novel CXCR5^–ICOS^hiPD-1^hi CD4 T cells may behave as aiCD4 T cells, and drive B cells and CD8 T cells to induce a variety of autoantibodies and lupus tissue injuries by producing massive IL-21.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibody-inducing-cd4-t-aicd4-t-cells-which-induce-systemic-lupus-erythematosus-sle-contain-follicular-helper-t-cell-in-addition-to-the-major-il-21-producing-cxcr5-icoshipd1hi-population-self/