Local networks of tissue-resident lymphocytes are strategically positioned in most anatomical compartments, including epithelial barrier surfaces such as the skin, the lung and the gut, where they provide immune surveillance and front-line defense to microbial invasion. In addition to immediate immunological effector activities, tissue-resident lymphocytes interact with both hematopoietic and non-hematopoietic cells and contribute to physiologic mechanisms of tissue homeostasis, repair and barrier function. The recently discovered innate lymphoid cells (ILCs) and tissue-resident memory T cells represent populations of prototypic lymphocytes that appear to adopt the fate of tissue-residency either “by default” during ontogeny, or, “as a result of induction” during peripheral differentiation, respectively. Under physiologic conditions, the size, microanatomical localization and subset composition of the local pools of lymphocytes differs quite dramatically among different organs, but the mechanisms that instruct cell-intrinsic adaptations and the development, maintenance and coordinated function of resident lymphocytes in specific tissue environments are poorly understood.
Innate Lymphoid Cells (ILCs): Our previous work revealed that the currently known subsets of ILCs are locally maintained as tissue-resident cells in all examined lymphoid and non-lymphoid organs (Gasteiger et al., Science 2015). The notion that ILCs form an integral part of their “host”-tissue suggests the presence of mechanisms of local development, differentiation and maintenance, as well as tissue-specific imprinting and specialization of ILCs.
Tissue-resident memory T (TRM) cells: We have recently identified antigen-dependent, “APC-proximal” competition of CD8+ T cells in non-lymphoid tissues as a mechanism that regulates the generation of local pools of memory T cells (Muschaweckh et al., J Exp Med 2016). These findings highlight local mechanisms for the “selection” or fine-tuning of a regional repertoire of resident memory cells that can optimally recognize and hence anticipate those antigens being present (and eventually presented) in the respective tissue, or, as suggested by our work, respective tissue regions. Such mechanisms may be critical to adapt the local pools of tissue-resident memory T (TRM) cells in response to regionally persisting pathogens, or to enable the local anticipation of tissue-invasion by regionally distinct microbial communities.
These complementary lines of research should enable us to delineate the nature of shared and cell-type specific characteristics of tissue-resident innate versus adaptive lymphocytes. In our quest to understand the development and maintenance of the “functional architecture” of local networks of tissue-lymphocytes, we are employing genetic mouse models, experimental models of inflammatory diseases, tumors and infection, single cell genomics and advanced imaging. We expect that our studies will contribute to a better understanding of the role of tissue-specific immunity in the regulation of immune homeostasis and defense.
Innate lymphocytes, including natural killer cells (NK) and recently discovered novel subsets of innate lymphoid cells (ILC) exert key functions in coordinating local immune responses, including the killing of infected cells, the production of hallmark cytokines that orchestrate immune responses, and the secretion of tissue-protective factors. Innate lymphocytes respond rapidly to environmental cues without the need for further differentiation. The ease of activation needs to be balanced by stringent control mechanisms because excessive activation of innate lymphocytes contributes to a loss of tissue function and facilitates inflammatory processes as well as the exacerbation of infection-associated pathologies.
The cellular interactions and the molecular mechanisms governing the regulation and activation of innate lymphocytes are therefore highly relevant for a broad range of physiologic and pathologic immune responses. Current research has largely focused on the role of innate cytokines and alarmins for the homeostasis and function of innate lymphocytes. In addition to their innate effector functions, ILC and NK cells have been found to participate in shaping and regulating adaptive immune responses. Whether the adaptive immune system may in turn contribute to the control of innate lymphocyte function and homeostasis is largely unknown. During our recent work, we have identified novel regulatory interactions between cells of the adaptive immune system and innate lymphocytes mediated by the “adaptive” cytokine IL-2. Our goal is now to determine the cellular mechanisms and the physiological relevance of these interactions using clinically relevant disease models. We are investigating additional pathways through which adaptive and innate lymphocytes may interact, as well as their potential therapeutic implications. Our aim is to understand the context-dependent physiological and pathological functions of innate lymphocytes for immune homeostasis as well as infectious and inflammatory diseases.
Publications (10 selected)
1. Muschaweckh A, Buchholz VR, Fellenzer A, Hessel C, König PA, Tao S, Tao R, Heikenwälder M, Busch DH, Korn T, Kastenmüller W, Drexler I*, Gasteiger G#*, “Antigen-dependent competition shapes the local repertoire of tissue-resident memory CD8+ T cells.“, J Exp Med. 2016 Dec 12;213(13):3075-3086.
2. Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY. “An essential role for the IL-2 receptor in Treg cell function.”, Nat Immunol. 2016 Nov;17(11):1322-133.
3. Bedoui S, Gebhardt T, Gasteiger G and Kastenmuller W, “Parallels between innate and adaptive lymphocytes - does being naïve make the difference?” Nat Immunol. 2016 May;17(5):490-4.
4. Gasteiger G#*, Fan D*, Dikyi S, Lee SY and Rudensky AY#, “Tissue residency of innate lymphoid cells in lymphoid and non-lymphoid organs.” Science 2015 Nov 20;350(6263):981-5.
5. Lu LF*, Gasteiger G*, Yu IS, Chaudhry A, Hsin JP, Bos PD, Lin LL, Zawislak CL, Cho S, Sun JC, Leslie CS, Lin SW and Rudensky AY, “A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner.” Immunity 2015 Jul 21;43(1):52-64.
6. Gasteiger G#, Rudensky AY#, “Interactions between innate and adaptive lymphocytes.” Nat Rev Immunol. 2014 Sep;14(9):631-9.
7. Feng Y, Arvey A, Chinen T, Van der Veeken J, Gasteiger G, and Rudensky AY, “Maintenance of regulatory T cell identity by a dedicated cis element in the Foxp3 locus.” Cell. 2014 Aug 14;158(4):749
8. Geiger TL, Abt MC*, Gasteiger G*, van den Brink MR, Pamer EG, Hanash AM, and Sun JC, “Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens.” J Exp Med. 2014 Aug 25;211(9):1723-31.
9. Gasteiger G, Hemmers S, Firth MA, Le Floc’h A, Huse M, Sun JC, and Rudensky AY, “IL-2 dependent tuning of NK cell sensitivity for target cells controlled by regulatory T cells.” J Exp Med. 2013 Jun 3;210(6):1167-78
10. Gasteiger G, Hemmers S, Bos P, Sun JC, and Rudensky AY, “IL-2 dependent adaptive control of NK cell homeostasis.” J Exp Med. 2013 Jun 3;210(6):1179-87
DFG Emmy-Noether Programm: Interactions of innate and adaptive lymphocytes
ERC Starting Grant: Tissue-resident Lymphocytes: Development and Function in ‚real-life‘ Contexts
DFG SPP 1937: Priority Programme Innate Lymphoid Cells