Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment

Abstract

TNFα inhibitors have shaped the landscape of rheumatoid arthritis (RA) therapy with high clinical efficiency. However, their impact on T cell recall responses is not well-elucidated. We aimed to analyze the immune profiles of memory T cells in RA patients undergoing TNFα inhibitor Golimumab (GM) treatment. Frequencies of peripheral T cell subsets and cytokine expression profiles in memory T cells (T M ) upon PMA/Ionomycine stimulation were determined by flow cytometry. Antigen-specific CD8 T cell immunity was analyzed through stimulating PBMCs with CMV-EBV-Flu (CEF) viral peptide pool and subsequent intracellular IFNγ staining. Both peripheral CD8 and CD4 T cells from GM treated patients had a shift pattern characterized by an enlarged effector T M and a reduced central T M cell population when compared to GM untreated group. An increase in the frequencies of TNFα + , IL-2 + , and IL-17 + CD8 T M cells was observed whereas only TNFα + CD4 T M cells increased in GM treated patients. Moreover, GM treated patients contained more peripheral IFNγ-producing CD8 T cells specific to CEF viral peptides. Together, these results show a distinct T cell subset pattern and enhanced memory T cell immunity upon GM treatment, suggesting an immunoregulatory effect of TNF inhibitor Golimumab on peripheral memory T cell responses.

Novel approaches to develop biomarkers predicting treatment responses to TNF-blockers

“…3A). An increased fraction of CD8+ T cells following anti-TNF treatment has also been recently described in RA patients [34]. The analysis also indicated that TNF-blockers may skew monocyte/macrophage polarization towards an M2 regulatory phenotype (Fig.…”

“…Increased effector responses after TNFi treatment has also been observed in RA patients (Table 2). Patients treated with golimumab showed an increase in the CD8+ T cell effector population, accompanied by increased responses to viral antigens, suggesting that TNF blockade, while broadly suppressing inflammation, does not induce generalized immunosuppression, but rather may "normalize" immune responses [34]. In agreement with this concept, anti-TNF treatment did not affect the expression of TNF-inducible genes in the site of acute inflammatory challenge (tuberculin injection), while decreasing the inducibility of these genes in blood samples [116].…”

Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming

“…As expected, there was a significant reduction of IL‐1β, IL‐6, and TNF‐α concentration in sera of CIA mice administrated with MB‐3 (Figure 3B). Previous studies showed that these proinflammatory cytokines were important in T cell proliferation and polarization, which contributed to the progress of RA 22,23 . Flow cytometric analysis revealed the reduction in both CD4 + and CD8 + T cell population that highly expressed CD44, a marker of murine memory T cells from MB‐3‐treated CIA mice (Figures 3C and D).…”

“…Previous studies showed that these proinflammatory cytokines were important in T cell proliferation and polarization, which contributed to the progress of RA. 22 , 23 Flow cytometric analysis revealed the reduction in both CD4 + and CD8 + T cell population that highly expressed CD44, a marker of murine memory T cells from MB‐3‐treated CIA mice (Figures 3C and D ). The imbalance between proinflammatory and anti‐inflammatory T cells populations dysregulated in RA leading to severe clinical outcomes.…”

MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis

“…In the current study, MALT1 was observed to reduce longitudinally during treatment, whose reduction correlated with RA treatment outcome (treatment response, low disease activity, or disease remission), which was in line with the previous study in IBD patients ( 14 ). The explanations are: (1) during treatment, the inflammation of RA is attenuated, then MALT1 closely relates to RA inflammation, so MALT1 is decreased together with inflammation ( 12 , 14 , 20 ); (2) bDMARDs or csDMARDs treatment may regulate multiple immune cells to affect MALT1 level in patients ( 29 , 30 ). The above data indicated the value of MALT1 measurement as a marker for disease monitoring of RA.…”