Warning — here comes a pathogen!

Credit: S.Bradbrook/NPG

Tissue-resident memory CD8⁺ T cells (T_RM cells) are important for the control of reinfection, but the mechanisms behind this have been unclear. Now, two studies published in Science show that following their activation, pathogen-specific T_RM cells rapidly induce a tissue-wide response that not only protects against the pathogen for which they are specific but also against unrelated pathogens.

Ariotti et al. investigated how a small number of T_RM cells can confer rapid protection of local tissue. They generated T_RM cells specific for a herpes simplex virus type 1 (HSV1) peptide in mice. To investigate if the T_RM cells had any effects on the surrounding tissue, the skin area harbouring the T_RM cells was challenged with the same HSV1-derived peptide or an ovalbumin control peptide. The transcriptional profiles from the entire skin tissue revealed differential expression of 89 genes between the two groups of mice. Of note, this differential gene expression was observed as early as 3 hours after antigen administration. Thus, reactivation of skin T_RM cells confers a rapid change in gene transcription in the entire skin tissue.

The authors found that the HSV1-derived peptide induced an increase in the level of expression of genes involved in inflammation and immunity. Further analysis indicated that interferon-γ (IFNγ) controls most of the transcriptional changes that are seen in the reactivated skin tissue. Indeed, the transcriptional response following T_RM cell reactivation in IFNγ-deficient mice was much lower than in control mice. Furthermore, the tissue response was lost in mice in which only the T_RM cells expressed the receptor for IFNγ. This indicates that reactivated T_RM cells express IFNγ that acts on other skin-resident cells.

Schenkel et al. used a similar experimental setup to study the mechanisms of T_RM cell-mediated immune responses to viral reinfection. They found that reactivation of T_RM cells led to increased expression of vascular cell adhesion molecule 1 (VCAM1) — which has a role in lymphocyte migration — on the local vascular endothelium. Similarly to Ariotti et al., the altered gene expression in response to T_RM cell reactivation depended on IFNγ, as VCAM1 was not upregulated when T_RM cells were reactivated in IFNγ-deficient mice.

reactivation of T_RM cells led to the maturation of dendritic cells

Next, B cells were shown to co-localize with T_RM cells within 12 hours of local T_RM cell reactivation and the number of B cells increased >100-fold by 48 hours. This recruitment was dependent on the production of IFNγ by locally reactivated T_RM cells and the induction of VCAM1 expression. Intracellular cytokine staining showed that T_RM cells also expressed tumour necrosis factor (TNF) after reactivation. Thus, reactivated T_RM cells may alert other immune cells to the presence of infection by producing cytokines. In fact, Schenkel et al. found that reactivation of T_RM cells led to the maturation of dendritic cells within 12 hours, which depended on TNF. Hence, activated T_RM cells can function as potent inducers of both adaptive and innate immune responses.

Finally, both research groups found that when reactivated T_RM cells were challenged with an unrelated pathogen the host showed protection against this secondary infection. Thus, they concluded that activation of T_RM cells depends on antigen recognition, but the genes that are upregulated in response to reactivation leads to local immune responses against antigenically unrelated pathogens.

Together, these studies show that the activation of T_RM cells induces tissue conditioning that leads to enhanced pathogen control. Furthermore, the results indicate that T_RM cells can sense previously encountered peptides and can broadcast that there is an infection without having to contact every infected cell. Thus, T_RM cells function as a bridge between the adaptive and innate immune systems.