Preprint Club
A cross-institutional Journal Club Initiative

Keywords

●  innate acting memory

●  heterologous immunity

●  bystander CD4+ T cell memory

Main Findings

Memory T cells allow more efficient clearance of pathogens upon re-infection, but our infection history also leaves an imprint on our immune system. During the course of our lives, we accumulate memory T cells and undergo naïve T cell attrition, which results in reduced T cell diversity. From this perspective, it becomes relevant to understand how the memory T cell repertoire can influence immune responses towards unrelated antigens. The contribution of bystander memory CD8+ T cells to immune responses has been already explored, and seems to be important in the context of infections (e.g. COVID-19) and inflammatory diseases. However, whether previously established memory CD4+ T helper cells also impact responses to heterologous infections was yet to be investigated.

In this preprint, Rakebrandt & Yassini et al. identified that the memory CD4+ T cell pool generated by an acute viral infection (LCMV) contains a subset of NKG2D+ and CXCR6+IL-18R+ CD4+ T cells that produces IFNγ upon IL-12 and IL-18 or IL-33 sensing. Since the IFNγ production was induced in a TCR-independent manner, authors termed this subset innate acting memory T (TIA) cells.

They dissected the functional role of this subset of memory T helper 1 (Th1) cells in two distinct contexts: a heterologous bacterial challenge (using Legionella pneumophila infection) and the EAE model of multiple sclerosis, an autoimmune disease. The results presented by Rakebrandt & Yassini et al. suggest that the outcome of memory CD4+ TIA activation is, as expected, context-dependent. These cells promote pathogen clearance upon heterologous infection, but accelerate the onset of disease during autoimmunity. This resulted both from their innate-like activation, but also from the preferential recruitment of CD4+ TIA cells to sites of inflammation. What regulates their migration to peripheral sites is still incompletely elucidated. Authors showed that these cells exhibit high expression of S1PR1 and low expression of CD69 in secondary lymphoid organs, which might benefit their egress and migration to tissues. Furthermore, they showed that cytokine activation can upregulate CD69 expression in CD4+ TIA cells. Because the cytokine milieu found in sites of infection and/or autoimmunity would lead to the activation of CD4+ TIA cells, authors speculate that this might be the mechanism how this subset is then retained in inflamed tissues.

In summary, CD4+ TIA cells represent a pro-inflammatory subset that can play a dual role: to promote the resolution of infections or to further tissue deterioration in autoimmunity. Future efforts should try to identify how to specifically boost or inhibit their function and/or promote or brake their development, which might make them potential targets of immunomodulation.

Limitations

●  CD4+ TIA cells are described as a subset of NKG2D+ and CXCR6+IL-18R+ CD4+ T cells. However, (1) NKG2D expression is not predictive of their function, (2) CXCR6 expression is a predictive of their function, but not of their migration potential and (3) IL-18R blockade in vivo only resulted in a slight reduction of IFNγ production. In summary, the none of the markers used to identify this subset are crucial for their function and migration profile.

●  Blocking antibodies used in some functional experiments likely do not solely impact on CD4+ TIA cell function.

●  Results suggest that CD4+ TIA cell migration is important for their function, but there is no direct evidence that this subset is long-term retained in the tissues after their recruitment. Authors show results from timepoints very early after heterologous re-challenge.

Significance/Novelty

T cell immunology has mostly focused on how TCR-specific responses occur. However, and especially in the context of inflammatory diseases and inflammaging, TCR-independent cytokine-driven bystander activation of T cells might also play a relevant role. Importantly, frequencies of memory T cells found in an individual increase over time as a consequence of their antigen exposure history. Thus, it becomes relevant to study features of memory T cells beyond their ability to respond to a re-challenge: do memory cells originated from previous infections impact on future immune responses to unrelated antigens? Is heterologous immunity protective? The bystander activity of CD8+ T cells has been previously explored, but in this preprint authors make a significant contribution towards a better understanding about how CD4+ T cell memory influences heterologous immunity in a cell-intrinsic manner. They were able to identify a subset of CD4+ T cell memory that they termed innate acting memory T (TIA) cells. These cells can be activated by specific cytokines and both promote clearance of unrelated pathogens but also worsen autoimmune diseases – their role is context-dependent. Such a dual role places this subset as a potential therapeutic target and highlights that we should consider TCR-dependent and TCR-independent mechanisms when developing immunomodulatory strategies.

Credit

Reviewed by Mariana Borsa as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.