Autoreactivity of Peripheral Helper T Cells in the Joints of Rheumatoid Arthritis

Abstract

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell–helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vβ usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self–MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling.

Phenotype‐Based Isolation of Antigen‐Specific CD4+ T Cells in Autoimmunity: A Study of Celiac Disease

“…T cells with the investigated phenotype (i.e., Tphe + cells), have increased frequency in the blood of several autoimmune conditions including rheumatoid arthritis and such T cells have been found to display autoreactivity in autoimmune hepatitis. [ 20,29,30 ] Thus, our findings represent a proof‐of‐concept for phenotype‐based isolation of disease‐specific CD4 + T cells in CeD that may be helpful in the identification of disease‐relevant CD4 + T cells in other autoimmune conditions.…”

Aberrant naive CD4+ T Cell differentiation in systemic juvenile idiopathic arthritis is committed to B cell help

“…Hence, we speculate that naïve Th cells isolated from active patients originate from an environment of high IL-18 as well as other pro-inflammatory cytokines, and consequently might be less prone to impaired Th1 cell differentiation. Yet, further studies are required to define whether these data indicate a rescued Th1 phenotype or the polarization toward a subset of IFNγ-expressing Tph/Tfh cells, as reported in context of rheumatoid arthritis(59). Nonetheless, regardless of disease activity status we observed elevated IL-21 release and a decreased IFNγ and Eomesodermin expression in developing Th cells even if cells underwent no stimulation other than by CD3/CD28-ligation.…”

ACPA-negative rheumatoid arthritis: From immune mechanisms to clinical translation

“…46 Peripheral helper T (Tph) (CXCR5 À PD1 + ) cells are a novel CD4 + subset with enhanced migratory capacity towards sites of inflammation and enhanced ability to promote antibody and proinflammatory cytokine production. 48,49 Intriguingly, levels of circulating Tph cells were similar between ACPA À RA and ACPA + RA. 46 These findings suggest that Tfh/Tph cells are also involved in the pathogenesis of ACPA À RA.…”