TIRC7 inhibits Th1�cells by upregulating the expression of CTLA‑4 and STAT3 in mice with acute graft‑versus‑host disease

Abstract

In a previous study, it was demonstrated that T-cell immune response cDNA 7 (TIRC7) levels reflect the efficacy of treatment of patients with acute graft-versus-host disease (GVHD). However, the pathogenesis of TIRC7 in acute GVHD remains poorly understood. Lymphocytes from patients with acute GVHD were selected as targeT cells, and the effects of TIRC7 on cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell activation and cytokine secretion were observed by electroporation. A mouse model of acute GVHD was established; anti-TIRC7 and anti-CTLA-4 monoclonal antibodies were intraperitoneally injected into recipient mice. Then, the effects of TIRC7 and CTLA-4 on T cell activation and acute GVHD were monitored. After TIRC7 expression was downregulated, CTLA-4 levels were decreased and STAT3 phosphorylation was reduced; conversely, the activation capacity of T lymphocytes was elevated, and the secretion of interferon-γ and other cytokines was increased. The mice in the TIRC7 + CTLA-4 co-administration group exhibited the lowest acute GVHD scores, with the longest average survival time and shortest recovery time of hematopoietic reconstitution. In conclusion, the results indicated that TIRC7 may positively regulate the function of CTLA-4 and inhibit T cell activation, thus suppressing the development and progression of acute GVHD.

Combination of STAT3 inhibitor with Herceptin reduced immune checkpoints expression and provoked anti‐breast cancer immunity: An in vitro study

“…An investigation has illustrated that STAT3 activation can lead to increased PD‐L1, CTLA‐4 and TIM‐3 expressions and immune response suppression 27,28 . A recent investigation on the role of TIRC7 (T‐cell immune response cDNA7) in STAT3 and CTLA‐4 expressions in T cells has revealed a new STAT3 regulator that confirmed the relationship between STAT3 and CTLA‐4 29 . It has also been shown that despite STAT3, upregulation of immune checkpoint factors could be among the mechanisms that the tumours resist Herceptin treatment 30,31 .…”

“…27,28 A recent investigation on the role of TIRC7 (T-cell immune response cDNA7) in STAT3 and CTLA-4 expressions in T cells has revealed a new STAT3 regulator that confirmed the relationship between STAT3 and CTLA-4. 29 It has also been shown that despite STAT3, upregulation of immune checkpoint factors could be among the mechanisms that the tumours resist Herceptin treatment. 30,31 To overcome this complication, we combined Herceptin with STAT3 inhibition and observed that STAT3 inhibition along with Herceptin can reduce the expression of the immune checkpoint factors more effectively, leading to a protective response towards cancer cell eradication.…”

STAT3 and SPI1, may lead to the immune system dysregulation and heterotopic ossification in ankylosing spondylitis

“…The activation of STAT3 may suppresses Th1 response during tuberculosis infection [ 23 ]. TIRC7 inhibits Th1 cells by upregulating the expression of CTLA‑4 and STAT3 in mice with acute graft‑versus‑host disease [ 24 ]. These results demonstrated that the upregulating of STAT3 may activate NKT cells and suppresses Th1 response.…”

Immune Regulatory 1 Cells: A Novel and Potent Subset of Human T Regulatory Cells

“…The co-stimulatory and co-inhibitory molecules CTLA-4 and ICOS are involved in the pathogenesis of autoimmune disease ( 36 , 37 ). TIRC7 is involved in regulation of CTLA-4, and its activation leads to increased CTLA-4 expression ( 11 , 38 , 39 ). IR1 cells show higher expression of both CTLA-4 and ICOS than do IR1neg Tregs.…”