Resident T cell memory
Project leader: Klaas van Gisbergen PhD
CD8 T-cells constitute an essential line of immune defense that mediates protection during viral infection and during tumor challenge in an antigen-specific manner. Upon infection, antigen-specific naive CD8 T-cells expand and differentiate into effector cells that establish viral clearance. CD8 T-cells are also important after resolution of infection, because of their capacity to develop into memory cells that provide enhanced protection upon secondary encounter with the pathogen. Tissue resident memory T cells (Trm) have recently been established as a key memory subset that independently of circulating memory T cells provide essential protection during secondary responses. Trm mediate protection after pathogen re-encounter through the early release of pro-inflammatory cytokines such as IFN-γ to establish activation of the surrounding tissue and the recruitment of other immune cells. An important aspect of the differentiation of Trm is the repression of egress pathways that enables these cells to permanently reside within the peripheral tissues. Trm completely lack expression of the tissue exit receptors S1PR1 and CCR7 that promote recirculation.
Universal regulation of resident lymphocytes
We reasoned that Trm and other resident lymphocytes such as NKT cells and innate lymphocytes (ILC) uniformly expressed a transcriptional repressor to mediate suppression of migratory pathways. Transcriptional profiling of resident and circulating lymphocytes from different tissues (skin, liver and gut) revealed that a limited number of transcription factors were specifically upregulated in the resident populations (Mackay, Science 2016; 352(6284):459-63). The analysis included a transcription factor encoded by the Zfp683 gene that we have previously described in NKT cells and that we have renamed Hobit (van Gisbergen, Nat Immunol 2012; 13(9):864-71). Hobit is highly homologous to Blimp-1, in particular within the DNA-interacting Zinc Finger domains, which are essential for repression of target genes. Consistent with the role of Blimp-1 in effector differentiation of B and T cells, we have previously described that Hobit regulated the terminal differentiation and effector function of NKT cells. Hobit and Blimp-1 were also essential for ILC development in liver and Trm development in skin, liver and gut. Thus, Hobit and Blimp-1 appear to act as universal transcription factors of tissue residency in lymphocytes (fig. 1).
Figure 1: The differentiation of Trm occurs through universal and tissue-specific factors. Naïve T cells differentiate into effector cells upon encounter with cognate antigen during infection. After clearance of infection, effector cells differentiate into memory cells. Central memory (Tcm) and effector memory (Tem) cells form circulating populations that can be distinguished from sessile tissue-resident memory (Trm) cells. Hobit and Blimp-1 are transcription factors that universally induce Trm formation, after which unknown tissue-specific factors drive the differentiation of Trm in different tissues to enable tissue-specific adaptations.
Resident T cell memory in cellular therapy
The recent realization that many T cells within the tissues permanently reside at these sites rather than circulate these and other tissues has radically changed fundamental concepts of T cell memory. The inability to circulate implies that resident memory T cells in contrast to circulating memory T cells form isolated populations in the skin, gut, liver, and other organs. This aspect of tissue-resident memory is conceptually relevant, as it enables these cells in contrast to circulating cells to fully adapt to the conditions of the local environment (Fig. 1). We hypothesize that Trm are better adapted than circulating memory cells to induce custom-made responses within the target tissue for optimal protection upon challenge with pathogens or tumor cells. Therefore, we anticipate that Trm can be developed into successful advanced therapy cellular products. The success of checkpoint blockade therapy, such as through the administration of anti-PD1 and anti-CTLA4 antibodies to cancer patients, suggests that recruitment of ‘exhausted’ tumor infiltrating lymphocytes including the tumor-resident Trm compartment into effective anti-tumor responses is feasible. Currently, a lack of knowledge on the potential of Trm hampers the use of these memory T cells in cellular therapies. We aim to improve fundamental insight into resident memory development to enable the future use of Trm in cellular therapies against infection and cancer.