CD4 T cells and B cell help – when exhausted cells can still function

Saggau C, Bacher P, Esser D, et al. Autoantigen-specific CD4(+) T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases. Immunity 2024;57:2416-2432.e2418 doi: 10.1016/j.immuni.2024.08.005

T-cell exhaustion is characterized by a lack of effector functions such as proliferation and cytokine secretion and was initially described in the context of chronic viral infection as a consequence of persistent antigen stimulation.¹ The impaired functionality is driven by signaling through inhibitory checkpoint receptors, PD-1 and CTLA-4 being the most prominent.² Similar mechanisms have been described in cancer, where exhausted T cells fail to control dysplastic cells, and the tumor microenvironment has been shown to be enriched with ligands for inhibitory receptors.³ Due to the great clinical success of checkpoint inhibitors, many details and different flavors of T-cell exhaustion have been identified. Yet, the majority of studies have focused on CD8 T cells, which are somewhat easier to study than CD4 T cells. Indeed, the frequencies of antigen-specific CD8 T cells in the circulation are higher and as front-line effector T cells their set of tasks is more clearly defined: expand and proliferate, clear infected or dysplastic cells and contract.

To expand our understanding of CD4 T cell biology, Saggau et al. investigated CD4 T-cell exhaustion in different autoimmune diseases, including autoimmune liver disease. Using an activation-based T-cell enrichment assay and direct ex vivo visualization with MHC class II tetramers, they identified and analyzed these extremely rare, circulating, antigen-specific CD4 T cells.⁴ They found that autoantigen-specific CD4 T cells exhibited an exhaustion-like phenotype characterized by reduced proliferative capacity and pro-inflammatory cytokine production, and upregulation of inhibitory receptors (PD-1, CTLA-4, TIGIT), while also expressing selected regulatory T-cell lineage markers, such as FoxP3 and Helios.

One of the study’s most intriguing findings is the observation that despite expressing classical features of T-cell exhaustion, both transcriptionally and on the protein level, autoantigen-specific CD4 T cells retain their B-cell helper capabilities, suggesting that this helper function is decoupled from the classical concept of T-cell exhaustion (Fig. 1). The observation of retained B-cell helper capabilities in the presence of otherwise dysfunctional T-cell responses also applies to chronic HCV infection. Notably, titers of neutralizing antibodies increase over time,⁵ although HCV-specific CD4 T cells are largely absent and those that are present display classical features of T-cell exhaustion.^6,7 However, the few HCV-specific CD4 T cells that can be detected also retain their B-cell helper function.⁸ Although chronic viral infections and autoimmunity are pathophysiologically very different conditions, they share a common feature from a T-cell perspective: chronic exposure to the cognate antigen – the viral protein and the autoantigen, respectively. In both disease settings, these cells appear to be maintained over years and decades, the mechanisms that govern this survival in the absence of classical markers of T-cell memory remain to be identified.

Fig. 1.

Retained B-cell help by chronically antigen-exposed CD4 T cells despite an exhaustion profile.

Persistent antigen stimulation, such as from autoantigens or viruses, can lead to reduced proliferation, impaired effector functions (e.g. decreased cytokine secretion), and increased inhibitory receptor expression in CD4 T helper cells. However, their capacity to provide B-cell help is preserved. (Created with BioRender.com).

The decoupling of B-cell helper functions from an exhausted phenotype raises questions about the general applicability of exhaustion markers for CD4 T cells. Unlike CD8 T cells, CD4 T cells serve diverse and more complex roles, differentiating into various helper subsets, such as Th1, Th2, Th17, regulatory T cells (Tregs) and follicular T helper (Tfh) cells, and thereby facilitate a wide range of immune functions.⁹ Tfh cells, for example, provide maturation signals to B cells in the lymphoid organs and are critical for the emergence of antibody responses. They constitutively express PD-1, secrete a rather limited set of cytokines and exhibit poor proliferative capacity.¹⁰ By CD8 T-cell standards, they would be classified as “exhausted”. Yet, the outcome of their work, namely class-switched high affinity neutralizing antibodies, is extremely efficient. Thus, given the pleiotropic functions of CD4 T cells, the concept of "exhaustion" is inherently more difficult to define in CD4 T cells.

As central regulators of both arms of the immune system, CD4 T cells are prime therapeutic targets. Although antigen-specific CD4 T cells appear to share so many features in autoimmunity and chronic viral infections, in a therapeutic context, they need to be driven in opposing directions. Indeed, while during chronic viral hepatitis, the goal would be to restore as many effector functions as possible to combat the persisting antigen, restoring tolerance to autoantigens would be the desirable outcome in autoimmunity. Thus, the study by Saggau et al. provides important insights into the dynamic and context-dependent nature of CD4 T-cell function and exhaustion. Future studies in different disease models are essential to further unravel the complexities of CD4 T-cell biology and identify additional pathways to target them therapeutically.

Authors’ contributions

Both authors contributed equally.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGPT (OpenAI) in order to improve grammar and style of the manuscript. After using this ChatGPT, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Financial support

This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): project 272983813 (TP04 to TBo).

Conflict of interest

The authors of this study declare that they do not have any conflict of interest.

Please refer to the accompanying ICMJE disclosure forms for further details.

Supplementary data

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