4.8 Review

The dichotomous outcomes of TNFα signaling in CD4+ T cells

Journal

FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.1042622

Keywords

tumor necrosis factor alpha; tumor necrosis factor receptor; T effector cells; T regulatory cells; pleiotropism; activation; costimulation; autoimmunity

Categories

Funding

  1. Human Islet Research Network (HIRN) Emerging Leader in Type 1 Diabetes(LMRF) [U24DK104162-07]
  2. American Cancer Society (ACS) Institutional Research Grant [IRG-19-137-20]
  3. South Carolina Clinical and Translational Research (SCTR) Pilot Project Discovery Grant [1TL1TR001451-01]
  4. Diabetes Research Connection (DRC) [IPF 22-1224]
  5. Beatson Foundation [2021-021]
  6. Northern California JDRF Center of Excellence [U24DK104162-07]
  7. [5-COE-2019-860-S-B]

Ask authors/readers for more resources

TNFa blocking agents, the first-in-class biologic drugs used for treating autoimmune diseases, have shown paradoxical exacerbation of autoimmunity in some patients. The complex signaling pathways of TNFa might explain the controversial findings of previous studies. Targeted manipulation of TNFa-TNF receptor signaling on select CD4(+) T cell subsets may offer specific therapeutic interventions for autoimmune diseases.
TNFa blocking agents were the first-in-class biologic drugs used for the treatment of autoimmune disease. Paradoxically, however, exacerbation of autoimmunity was observed in some patients. TNFa is a pleiotropic cytokine that has both proinflammatory and regulatory effects on CD4(+) T cells and can influence the adaptive immune response against autoantigens. Here, we critically appraise the literature and discuss the intricacies of TNFa signaling that may explain the controversial findings of previous studies. The pleiotropism of TNFa is based in part on the existence of two biologically active forms of TNFa, soluble and membrane-bound, with different affinities for two distinct TNF receptors, TNFR1 and TNFR2, leading to activation of diverse downstream molecular pathways involved in cell fate decisions and immune function. Distinct membrane expression patterns of TNF receptors by CD4(+) T cell subsets and their preferential binding of distinct forms of TNF alpha produced by a diverse pool of cellular sources during different stages of an immune response are important determinants of the differential outcomes of TNFa-TNF receptor signaling. Targeted manipulation of TNFa-TNF receptor signaling on select CD4(+) T cell subsets may offer specific therapeutic interventions to dampen inflammation while fortifying immune regulation for the treatment of autoimmune diseases.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available