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Deciphering the immune signature of SepSecs-specific CD4 T cells in autoimmune hepatitis: what do we know and what remains to be done?

Submitter: Amédée Renand | amedee.renand@univ-nantes.fr

Authors: Amédée Renand, Sophie Conchon, and Pierre Milpied

Nantes Université, INSERM UMR1064 – Center for Research in Transplantation and Translational Immunology; Aix Marseille Université, CNRS, Centre d’Immunologie de Marseille-Luminy

Published February 25, 2025

In their recent publication in The Journal of Clinical Investigations, Kramer et al provide an analysis of B and T cell repertoires targeting the SepSecs antigen (Soluble liver antigen; SLA) in patients with autoimmune hepatitis (AIH) (Kramer et al. J Clin Invest. 2025). Yasumizu et al, in their accompanying commentary, highlight the need for further investigation into the specific phenotype of SepSecs (SLA) specific CD4 T cells (Yasumizu et al. J Clin Invest. 2025). They propose using advanced techniques such as single-cell RNA sequencing and TCR characterization to understand the complexities of these immune cells. Here we would like to point out important findings in that field that have already been published and seem to have been omitted by Yasumizu et al.

In 2020, our team conducted an integrative analysis of Sepsecs-specific CD4 T cells in the blood of AIH patients (Renand et al. J. Hepatol. 2020). Our study compared AIH patients with and without anti-SLA antibodies, examining their CD4 T cell response to SepSecs and Candida albicans MP65 peptides. Only AIH patients with anti-SLA antibodies showed significant memory Sepsecs-specific CD4 T response. Single-cell RNA sequencing analysis using FB5P-seq revealed distinct transcriptomic signatures between MP65-specific and SepSecs-specific memory CD4 T cells. While MP65-specific cells showed a typical TH17 signature, SepSecs-specific CD4 T cells expressed IL21, IFNG, and multiple immune checkpoint genes (TIGIT, CTLA4), resembling T peripheral helper cells known to support B cell responses in autoimmune conditions. The parallel analysis of transcriptome and TCR sequences demonstrated clear clonal expansion patterns among these cells.

In conclusion, the integration of transcriptomics and TCR sequencing offers unprecedented opportunities to study antigen-specific T cells in various immunological contexts. Based on our current knowledge, the crucial next steps will be to elucidate the phenotype of SepSecs-specific CD4 T cells directly in liver tissue. This represents a major scientific and methodological challenge but is key to a more complete understanding of AIH pathogenesis.

Our recent work is in line with this concept, demonstrating the close links between circulating autoreactive CD4 T cells and autoimmune processes occurring in the liver of AIH patients (Cardon et al. Nat Commun 2025). In this study, we discovered that autoreactive memory circulating CD4 T cells and dominant intrahepatic CD4 T cell clones found in the blood, exhibited a similar ex vivo immune signature associated with chronic antigen stimulation in the tissue.

The authors have declared that no conflict of interest exists.