Precursors of exhausted T cells are pre-emptively formed in acute infection, 2025, Chu et al

[Sly Saint]

Even in the case of uncomplicated infections, the body prepares itself early on for the possibility of a more severe course. A research team from the Technical University of Munich (TUM) and Helmholtz Munich has now uncovered this mechanism. The scientists showed that, right at the onset of mild illness, the body also produces special T cells previously known only from chronic, severe infections and tumors.

There are different types of T cells in the body, all of which play a crucial role in the immune system. They fight pathogens and control the immune response. However, some subtypes become less effective or even cease their activity altogether as the disease progresses. This has a protective function: in persisting infections, it would harm the body if the immune system continued to fight the pathogens aggressively. However, T cell exhaustion is a problem in the treatment of cancer, as therapeutic measures may no longer be effective.

Until now, it was assumed that the body only produces such T cells in severe and persisting infections. The results of the researchers at TUM and Helmholz Munich show that this is not the case.

We were able to show that the body prepares T cell subtypes that are predisposed to exhaustion even in early infection phases of moderate diseases."

Dietmar Zehn, Professor of Animal Physiology and Immunology at TUM and last study author

Scientists find early signs of T cell exhaustion in early infection stages

paper:
Precursors of exhausted T cells are pre-emptively formed in acute infection | Nature

 

[Jonathan Edwards]

As I suspected, 'T cell exhaustion' was not a very useful term!

 

[Hutan]

Abstract
T cell exhaustion limits effector T cell function in chronic infection and tumours. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions that are met only after persistent exposure to antigen and inflammation.

Here we show, however, that similar T cell populations exist in the early phase of acute infections. At that stage, the early developing TCF1+ precursor population exhibits an unexpected diversity; it includes precursors of normal memory T cells, but also cells with phenotypic, gene-expression and epigenetic profiles that resemble those of precursors of exhausted T cells found in chronic infections.

We show that high ligand affinity promotes and PD-1 signalling restricts the development of these precursors. Although the exhausted precursors are at first found frequently, they decline without being completely lost in infections that the immune system resolves. We therefore conclude that precursor T cells with at least two distinct phenotypes are pre-emptively generated irrespective of the outcome of an infection.

Link open access

 

[Hutan]

T cell exhaustion refers to the formation of hypofunctional T cells with a reduced effector function and reduced potency in eliminating target cells in the setting of prolonged antigen exposure in chronic infec-tions and tumours. Characterized by a reduced cytokine-secretion capacity and upregulated expression of inhibitory receptors (PD-1, LAG3, 4-1BB or OX40)1–4, exhausted CD8 T cells also express a unique pattern of transcription factors, which includes high levels of TOX, NR4A1, NR4A2 and EOMES, and lower levels of T-bet (refs. 5–12) and of hypoxia-inducible factor 1α (HIF-1α)13.

Moreover, the hypofunctional phenotype is epigenetically enforced and ‘exhaustion’ imprints are retained even when cells are transferred from chronic into acute infections14, and after their reactivation through checkpoint inhibi-tors2,15–18. Although this exhausted state is crucial for preventing immunopathology in the context of chronic antigen stimulation, the low effector capacity of exhausted T cells is a major obstacle for effective immunotherapy against chronic infections and tumours19–21. Under-standing the kinetics and mechanisms that drive the induction and maintenance of exhausted T cells is therefore essential for devising advanced immunotherapeutic solutions that aim to prevent or over-come their development.

Cluster 2 (day 4.5) contained a combination of markers of progenitor cells (Tcf7, Slamf6 and Id3) and markers of T cell exhaustion (Xcl1, Pdcd1 and Tox).

T cells in the day-4.5 restricted cluster 3 (Fig. 1b) expressed high levels of early activation markers, including Xcl1 and Myc, high levels of well-known genes associated with exhaustion, such as Pdcd1, Tox, Tnfrsf9 (4-1BB), Myb and Havcr2 (TIM3), low levels of traditional effector molecules (Id2, Tbx21, Cxcr6 and Ccr5) and reduced levels of granzymes (Gzma, Gzmk and Gzmm) (Fig. 1b,c).

Thus, the phenotype of cells found in clusters 2 and 3 suggests that cells with transcriptional similarity to that seen in T cell exhaustion are detectable in the early phase of acute infection. This encouraged us to examine the origin and fate of these cells in more detail.