MHC class I Ion target cells regulates CD4+ T cell-mediated immunity

Sep 22, 2026

MHC class I molecules are revealed to control CD4+ T cell-mediated immunity through a mechanism distinct from antigen presentation to CD8+ T cells. In allogeneic graft-versus-host disease and tumor models, absence of MHC class I on target cells markedly increases vulnerability to CD4+ T cell cytotoxicity, linked to heightened sensitivity to ferroptosis. Human transcriptomic datasets further suggest that downregulation of MHC class I can enhance responses to immune checkpoint blockade in melanoma and mismatch-repair-deficient colon cancers.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages34

Reading Time1 h 26 min

AccessFree to download

Background

MHC class I and class II antigen presentation

Known functions beyond antigen presentation

Research Question

MHC class I role in direct CD4+ target cell lysis

Link to ferroptosis and iron-dependent cell death

Results

MHC I expression regulates CD4+ T cell-mediated immunopathology

Experimental models for GVHD and MHCI deficiency

nature immunology Article [https://doi.org/10.1038/s41590-026-02480-z](https://doi.org/10.1038/s41590-026-02480-z) MHC class Ion target cells regulates CD4+ T cell-mediated immunity Received: 17 April 2025 Accepted: 26 February 2026 | Published online: 24 March 2026 | | --- | | Check for updates | Emma Lauder1,2,10, Mahnoor Gondal3,4,10, Meng-Chih Wu 2,5,10, Akira Yamamoto 2, Laure Maneix 2, Dongchang Zhao2, Yaping Sun2, Marcin Cieslik3,4,6,7, Arul M. Chinnaiyan 3,4,6,7,8,9 & Pavan Reddy 2 Major histocompatibility complex (MHC) class I and class II molecules present antigens to CD8+ and CD4+ T cells respectively. Here we uncover a previously unrecognized role forMHC class I in modulating CD4+ T cell-mediated immunity. In allogeneic graft-versus-host disease and tumor models, we demonstrate that the absence of MHC class Ion target cells significantly increases their susceptibility to CD4+ T cell cytotoxicity. Transcriptomicand functional studies suggest that this was because of heightened sensitivity to enhanced ferroptosisofthe target cells. In large human transcriptomicand sequencing datasets, a role for CD4+ Tcells in enhancing immune checkpoint blocker-mediated responses in persons with melanoma and mismatch-repair-deficient colon cancers that have downregulated MHCclass I was suggested. These findings revise and expand the known role of MHC class IinCD8+ T cell and natural killer cell immunity and demonstrate a previously unrecognized role in CD4+ T cell-mediated cancer and alloimmunity. First studied in the context of allogeneic transplantation, the major histocompatibility complex (MHC) is central to adaptive immune responses. MHC presents antigenic peptideson the cell surface forT cell recognition. This process shapesT cell ontogeny and function by followinga class-restricted dichotomy where MHCclassI (MHCI) is restricted to driving CD8+ T cell immunity and MHCIIto CD4+ Tcell immunity1. While MHCIIis restricted to antigen-presenting cells (APCs), MHCI is ubiquitously expressed on all nucleated cells for primary surveillance. Consequently, viruses and tumors frequently downregulate MHC Ito evade immune surveillance. Beyond antigen presentation, MHC I regulates CD8+ T cell and natural killer (NK) cell function2, as well as nonimmune processes, including neuronal pruning, placental development, iron homeostasis andoverload (hemochromatosis)3–5. However, given that MHC I is expressed by all nucleated cells, whether MHCI has a role independent of antigen presentation to CD8+ T cells, specifically in direct CD4+ T cell-mediated target cell lysis, is not known. Herein, we investigated whether the presence of MHC Iona target cell modifies the activation of CD4+ Tcells and/orthe sensitivity and responsiveness of the target cells exclusively to CD4+ T cells. Furthermore, while mutationsintheHFE gene have a rolein iron biology and hereditary hemochromatosis6, whether MHCI loss offunction leads to enhanced iron-dependent cell death, known as ferroptosis, remains unknown. Recent data have demonstrated a key role for ferroptosis in CD4+-mediated and CD8+-mediated infection and tumor immunity7. However, its role in alloimmunity (allogeneic immune response) remains unexplored. While iron overload has been linked to ferroptosis8,9, it is unknown whether MHC I expression, regardless of iron overload, regulates susceptibility to ferroptosis. Using multiple well-characterized and clinically relevant models of allogeneic graft-versus-host disease (GVHD) and immunologically stringent models of tumor immunity, we explored whether MHC I expression on target cells regulated CD4+ T cell-mediated immunity 1Immunology Program, University of Michigan, Ann Arbor, MI, USA. 2Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. 3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. 4Michigan Center for Translational Pathology, Univers

FAQs

What role does MHC class I play in CD4+ T cell-mediated immunity according to the study?

MHC class I on target cells regulates CD4+ T cell-mediated immune responses by inducing target cell ferroptosis, rather than only supporting CD8+ T cell or NK cell immunity.

How did the study test the effect of MHC class I absence on CD4+ T cell cytotoxicity?

It used allogeneic GVHD and tumor models, comparing target tissues lacking MHC class I (via β2-microglobulin knockout recipients) with wild-type recipients to isolate CD4+ T cell effects.

What is the proposed mechanism behind increased susceptibility of MHC class I-deficient target cells?

Transcriptomic and functional studies suggest heightened sensitivity to ferroptosis in the target cells.

Sep 22, 2026

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