Interferon Disrupts AHR-JUN Axis to Induce CXCL13-Producing T Cells in Systemic Lupus Erythematosus

Conceitos essenciais

Type I interferon opposes the AHR-JUN axis to promote the expansion of CXCL13-producing T follicular helper and T peripheral helper cells, contributing to the pathogenesis of systemic lupus erythematosus.

Resumo

The article investigates the regulation of CXCL13-producing T cells in systemic lupus erythematosus (SLE), a prototypical autoimmune disease driven by pathological T cell-B cell interactions. The authors identify an imbalance in CD4+ T cell phenotypes in SLE patients, with an expansion of PD-1+/ICOS+ CXCL13+ T cells and a reduction of CD96hi IL-22+ T cells.

Using CRISPR screens, the authors find that the aryl hydrocarbon receptor (AHR) is a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic, and functional studies demonstrate that AHR coordinates with the AP-1 family member JUN to prevent CXCL13+ T follicular helper (TFH) and T peripheral helper (TPH) cell differentiation and promote an IL-22+ T helper 22 (TH22) phenotype.

Importantly, the authors show that type I interferon, a pathogenic driver of SLE, opposes the AHR-JUN axis to promote T cell production of CXCL13. These findings place CXCL13+ TFH/TPH cells on a polarization axis opposite from TH22 cells and reveal AHR, JUN, and interferon as key regulators of these divergent T cell states in the context of SLE.

Estatísticas

Expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells in SLE patients.
AHR is a potent negative regulator of CXCL13 production by human CD4+ T cells.

Citações

"Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE."
"Type I interferon, a pathogenic driver of SLE, opposes AHR and JUN to promote T cell production of CXCL13."

Principais Insights Extraídos De

Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus - Nature

by Calvin Law,V... às www.nature.com 07-10-2024

https://www.nature.com/articles/s41586-024-07627-2

Perguntas Mais Profundas

How do the AHR-JUN axis and type I interferon signaling pathways interact to regulate the balance between CXCL13+ TFH/TPH cells and IL-22+ TH22 cells in the context of other autoimmune diseases?

In the context of autoimmune diseases, the AHR-JUN axis and type I interferon signaling pathways play crucial roles in regulating the balance between CXCL13+ TFH/TPH cells and IL-22+ TH22 cells. The AHR-JUN axis acts as a negative regulator of CXCL13 production by human CD4+ T cells, thereby inhibiting the differentiation of CXCL13+ TPH/TFH cells. On the other hand, type I interferon, a known pathogenic driver of systemic lupus erythematosus (SLE), opposes the actions of AHR and JUN to promote the production of CXCL13 by T cells. This results in an imbalance in CD4+ T cell phenotypes, with an expansion of PD-1+/ICOS+ CXCL13+ T cells and a reduction of CD96hi IL-22+ T cells. Therefore, the interplay between the AHR-JUN axis and type I interferon signaling pathways determines the differentiation and abundance of CXCL13+ T cells versus IL-22+ T cells in autoimmune diseases like SLE.

What are the potential therapeutic implications of targeting the AHR-JUN axis or type I interferon signaling to modulate the CXCL13+ T cell population in SLE and other autoimmune disorders?

Targeting the AHR-JUN axis or type I interferon signaling pathways could have significant therapeutic implications for modulating the CXCL13+ T cell population in systemic lupus erythematosus (SLE) and other autoimmune disorders. By manipulating these pathways, it may be possible to restore the balance between CXCL13+ TFH/TPH cells and IL-22+ TH22 cells, which is disrupted in autoimmune diseases. For instance, enhancing AHR activity or inhibiting interferon signaling could potentially reduce the production of CXCL13 by T cells, thereby limiting the expansion of pathogenic CXCL13+ T cells in SLE. This targeted approach could help in rebalancing the immune response and potentially ameliorating autoimmune pathology associated with aberrant T cell populations.

Could the insights from this study on the regulation of CXCL13-producing T cells be applied to understand the role of these cells in the context of infectious diseases or cancer immunology?

The insights gained from studying the regulation of CXCL13-producing T cells in autoimmune diseases like systemic lupus erythematosus (SLE) could indeed be applied to understand the role of these cells in the context of infectious diseases or cancer immunology. CXCL13 is a B cell chemoattractant produced by T follicular helper (TFH) and T peripheral helper (TPH) cells, which are involved in providing help to B cells. In infectious diseases, understanding the regulation of CXCL13 production by T cells could shed light on how these cells contribute to the immune response against pathogens. Similarly, in cancer immunology, where the tumor microenvironment can influence T cell differentiation and function, insights into the factors that control CXCL13 expression could aid in deciphering the interactions between T cells and tumor cells. Therefore, the findings regarding CXCL13-producing T cells in autoimmune diseases may have broader implications for understanding T cell responses in the context of infectious diseases and cancer.