Our bodies are protected from infection and disease by several different types of immune cells. Gamma delta T cells are unusual in that they only make up a small proportion of the immune cells of the body, yet are present in many different animal species. These peculiar T cells are primarily found in the tissues that line the body (such as the skin, lung and gut) and are part of the first stage of the immune response that occurs when an invading microbe enters the body.

Gamma delta T cells, like all other T cells, develop in an organ called the thymus, which is found in the chest. Although several complex signaling pathways have been identified that help specific immune cells to develop, there are still many open questions about them. It is also unclear if other cells in the thymus influence how gamma delta T cells develop.

Mair et al. engineered mouse embryos that could not produce a signaling molecule known as NIK in certain subsets of their cells. This revealed that NIK is important for a structural cell in the thymus to instruct the early stages of gamma delta T cell development. However, gamma delta T cells themselves do not need to be able to produce NIK or the signaling pathway that it triggers.

Further work will focus on discovering the exact way in which the structural cells of the thymus interact with gamma delta T cells. This will help us understand better how developing immune cells are ‘educated’ in the thymus so that they are able to work effectively in the adult.

γδ T cells, together with αβ T cells and B cells, are the only cells in mammals capable of generating diverse antigenic receptors by somatic gene rearrangement, which enables them to specifically recognize and respond to a vast array of antigens. However, while the essential role of αβ T cells and B cells for the induction of long-lasting protective immune responses is undisputed, γδ T cells due to their low abundance in peripheral lymphoid organs have been often ignored by the scientific community (Allison and Havran, 1991). This has changed in the past decade, as it became evident that γδ T cells are important players not only during protective immune reactions (Lockhart et al., 2006), but also in various models of autoimmune disease (Petermann et al., 2010; Cai et al., 2011; Pantelyushin et al., 2012).

Several features distinguish γδ T cells from their αβ counterparts (reviewed in Vantourout and Hayday, 2013). Most notably, γδ T cells recognize qualitatively different antigens. The scope of the potential antigens has not been revealed entirely, but known targets include non-classical MHC molecules (Strid et al., 2008), phosophoantigens (Constant et al., 1994) as well as a discrete set of non-self proteins (Zeng et al., 2012). The second main characteristic of γδ T cells is their ability for rapid production of pro-inflammatory cytokines such as INF-γ and IL-17 independent of TCR engagement (Sutton et al., 2009). This feature has been suggested to be hardwired in developing γδ T cells already during thymic development, probably in dependency of self-antigen recognition (Jensen et al., 2008). The surface molecule CD27, which belongs to the tumor necrosis (TNF) receptor superfamily has been shown to distinguish IFN-γ-producing from IL-17-producing γδ T cells (Ribot et al., 2009), as does the differential expression of the transcription factors T-bet and RORγt and certain chemokine receptors such as CCR6 (Haas et al., 2009).

Although the genetic diversity of the TCR γδ locus would theoretically allow an even higher number of different TCR specificities than for αβ T cells (Bonneville et al., 2010), γδ T cells show a remarkable limitation in their TCR variability. Moreover, γδ T cells with a given TCR specificity often home to non-lymphoid organs, where the majority of mature γδ T cells can be found. The prime example of tissue homing-behavior is observed in dendritic epidermal T cells (DETCs), which are found in the murine epidermis and almost exclusively express a clonotypic TCR consisting of the Vγ5 and Vδ1 chains (Asarnow et al., 1988). Vγ5⁺ DETCs are among the very first T cells to develop during embryogenesis, populating the epidermis already around day 15/16 of fetal development (Xiong et al., 2004). Also other subsets of γδ T cells, such as Vγ4⁺ γδ T cells (mostly IL-17 producers), which migrate predominantly to the dermis and lung tissue, have been shown to develop only early in ontogeny (Allison and Havran, 1991; Haas et al., 2012; Prinz et al., 2013).

The underpinning signaling pathways and precise developmental program as well as the mechanisms underlying the pre-determined cytokine profile of γδ T cells have been only partially resolved. One major step forward was the identification of Skint-1 (Selection and upkeep of intraepithelial T cells-1), which has an essential function for the development of Vγ5⁺ DETCs (Lockhart et al., 2006; Lewis et al., 2006; Boyden et al., 2008). Expression of Skint-1 by medullary thymic epithelial cells (mTECs) (Barbee et al., 2011) leads to a signaling cascade in developing γδ thymocytes that induces the typical gene expression profile of DETCs, concomitant to their preferential homing to the skin (Turchinovich and Hayday, 2011; Vantourout and Hayday, 2013). On the other hand, the induction of the typical gene signature of IL-17-producing Vγ4⁺ γδ T cells depends on the function of the transcription factor Sox13 (Gray et al., 2013), while the required receptors remain elusive.

It has been known for some time that signaling pathways leading to activation of NFκB are essential for the function of various immune cell compartments (reviewed in Li and Verma, 2002). The so-called classical pathway of NFκB activation is induced mainly by molecular danger signals such as LPS or certain cytokines such as TNF or IL-1β. Non-canonical NFκB signaling, which requires the NFκB-inducing kinase (hereafter referred to as NIK, the encoding gene being Map3k14,) (Malinin et al., 1997; Yin, 2001) is activated by a discrete subset of TNF family members, including CD40L, Lymphotoxin (LT), BAFF (B cell activating factor) and RANKL (Receptor activator of NFκB ligand). Signaling via the non-canonical pathway has been shown to fulfill roles in B cell survival (Sen, 2006), activation of T cells (Matsumoto et al., 2002; Ribot et al., 2009), maturation and function of dendritic cells (DCs) (Hofmann et al., 2011) as well as the induction of tolerance (Zhu et al., 2006; Bonneville et al., 2010), but it has not been studied in the context of γδ T cell biology in detail. Previous work has suggested that signaling via the CD70-CD27 axis (which belongs to the tumor necrosis factor receptor superfamily) can activate NFκB p52 processing (Ribot et al., 2010). Also, LTβR signaling has been implicated in the differentiation program of bulk γδ thymocytes (Silva-Santos, 2005), and the NFκB family members RelA and RelB were shown to guide the development of IL-17-producing Vγ4⁺ γδ T cells (Powolny-Budnicka et al., 2011). Furthermore, the genesis of invariant NKT cells was claimed to depend on signaling via NIK (Elewaut et al., 2003).

In the present study we set out to systematically analyze the impact of non-canonical NFκB signaling on the development and function of γδ T cells. In line with previous studies that were using knockout models of the TNF receptor family member RANKL (Roberts et al., 2012) we found that NIK-deficient mice showed a drastic loss of DETCs in the epidermis. Of note, in the absence of NIK most of the IL-17 production by splenic and lung-resident γδ T cells was lost, while their ability to express IFN-γ was not affected. Mechanistically, this was accompanied by a loss of Rorc and Sox13 expression in NIK-deficient CD27^- γδ T cells, while in turn expression of Tbet and Egr3 was increased. While previous studies reported trans-conditioning of developing γδ T cell precursors by CD4⁺ thymocytes (Silva-Santos, 2005; Powolny-Budnicka et al., 2011), our data suggest that NIK signaling specifically in thymic epithelium is essential for shaping the cytokine profile of the γδ T cell compartment.

In the past years, γδ T cells have attracted growing interest due to their unique features that place them at the interface of adaptive and innate immunity. Nevertheless, in contrast to αβ T cells, the signaling events underlying γδ T cell development and activation are much less understood (reviewed in Prinz et al., 2013 and Vantourout and Hayday, 2013). Here, we have shown in vivo that NIK signaling in thymic epithelial cells is essential for the full function of two different γδ T cell populations, namely skin-resident DETCs as well as CD27^- IL-17-producing γδ T cells.

Previous work has suggested an involvement of the NFκB-inducing kinase in the differentiation of both αβ and γδ T cells (Eshima et al., 2014). Contrary to the findings by Eshima and colleagues we could not observe a consistent overall reduction in the number of γδ T cells (except the DETC pool), yet we observed functional impairment of CD27^- IL-17-producing γδ T cells. This discrepancy might result from two mutually non-exclusive explanations: first, aly/aly mice as well as Map3k14^-/- mice due to their complex phenotype (including impairment of thymic negative selection) are prone to develop some degree of tissue inflammation over time, which is accompanied by an expansion of both CD4⁺ and CD8⁺ cells (Tsubata et al., 1996; Ishimaru et al., 2006; Zhu et al., 2006) and could thereby induce a relative decrease in the proportion of γδ T cells. Second, it has recently been established that the γδ T cell compartment cannot be fully reconstituted using bone-marrow chimeric animals (Gray et al., 2011; Haas et al., 2012). Using a genetic model that allows the cell-type specific deletion of NIK avoids all these confounding phenotypes of mice in which the gene locus of NIK (Map3k14) has been deleted in the germ-line.

Two members of the TNFR family, namely CD40 and RANK, have been implicated both in the development of DETCs and full maturation of mTECs (Hikosaka et al., 2008; Akiyama et al., 2008). In embryogenesis, these events occur at similar time points post conception, and it seems that in the embryonic thymus, developing DETC precursors signal via the RANKL-RANK axis to immature mTECs, inducing their full maturation to Aire⁺ MHC-II^high mTECs (Roberts et al., 2012). Hence, Tnfrsf11a^-/- mice have reduced numbers of DETCs. Given that NIK is downstream of RANK (Darnay et al., 1999), one would expect a similar phenotype in Map3k14^-/- animals, but the DETC deficiency that we observed in newborn Map3k14^-/- mice was much more pronounced than in Tnfrsf11a^-/- animals, suggesting that during DETC development several upstream receptors converge in their signaling to NIK, making it a key pathway during thymic DETC development. Importantly, our data obtained using the conditional NIK-mutant strongly suggests that for normal function of the γδ T cell compartment, NIK signaling does not act γδ cell-intrinsically but in trans by its function in thymic epithelial cells. Conditional deletion of NIK solely in thymic epithelial cells was sufficient to copy the DETC phenotype seen in complete germ-line NIK-knockout animals. We believe this to be the first genetic in vivo demonstration that non-canonical NFκB signaling is not required in DETCs in a cell-intrinsic manner, but through its activity in TECs.

The ability of CD27^- γδ T cells to rapidly produce IL-17 even after being activated only by cytokines (Sutton et al., 2009; Ribot et al., 2009) has been the focus of intense research. Only the neonatal thymic microenvironment appears to have the capacity to imprint a stable cytokine profile to γδ T cells, since the IL-17-producing γδ T cell subsets cannot be reconstituted in adult animals by bone marrow transfer (Haas et al., 2012). Very recently, a hallmark paper has provided mechanistic insights into how this can be achieved: during embryonic development of certain γδ T cell subsets, the signaling threshold for activation of the TCR becomes markedly altered (Wencker et al., 2013). Hence, mature γδ T cells do not necessarily rely on a TCR stimulation as “‘signal one”’, although they can still respond to that (Strid et al., 2011).

However, while this intriguing mechanism (Wencker et al., 2013) explains the behavior of several γδ T cell subsets, the thymic cues orchestrating this hard-wiring of γδ T cells remain unclear. Previous work suggested either LTβR-dependent trans-conditioning by double positive thymocytes or γδ T cell intrinsic RelB activation (Silva-Santos, 2005; Powolny-Budnicka et al., 2011). Further work by Silva-Santos and colleagues emphasized the role of TNF-receptor family members such as CD27 as well as NFκBp52 activation (Ribot et al., 2010). However, the contribution of thymic stromal cells to these processes has not been experimentally addressed in vivo. Our data suggest that NFκB signaling via NIK seems to be dispensable both within CD27^- γδ T cells as well as αβ T cells, at least for their ability for expression of pro-inflammatory IL-17. Of note, deletion of NIK in all thymic epithelial cells using Foxn1-Cre phenocopied the complete NIK-knockout in terms of IL-17 expression by CD27^-γδ T cells, while this was not the case using Ccl19-Cre. The latter has been reported to target only maturing medullary thymic epithelial cells (Onder et al., 2015). This would suggest that the instruction of γδ T cells is mediated by early or junctional TECs, or that the timing of Ccl19-Cre-mediated recombination sharply coincides with the expression of the γδ T cell instructing program in TECs. Based on our observation that NIK signaling in the early thymic stroma has a profound and long-lasting effect on the maturation and cytokine profile of developing γδ T cells, further studies are required in order to precisely define the nature of γδ T cell instructing molecules, and which thymic epithelial cell type is required for delivery. While our data does not exclude a role for canonical-NFκB signaling via RelA (Powolny-Budnicka et al., 2011), the impact of non-canonical signaling via NIK on the development of DETC precursors and IL-17-producing γδ T cells stems from signaling within the thymic stroma, for which the conditional NIK mutant is a unique tool for further studies. Future work will reveal whether NIK-deficient thymic stroma influences only γδ T cell development, or also the functional profile of the subsequently emerging αβ T cell compartment.

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Author details

1. Florian Mair

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

   Contribution

   FM, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Stefanie Joller

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

   Contribution

   SJ, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-6906-4892

3. Romy Hoeppli

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

   Present address

   Department of Surgery, Child and Family Research Institute, University of British Columbia, Vancouver, Canada

   Contribution

   RH, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Lucas Onder

   Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland

   Contribution

   LO, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Matthias Hahn

   Institute for Molecular Medicine, University Medical Center, Johannes-Gutenberg University of Mainz, Mainz, Germany

   Contribution

   MH, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Burkhard Ludewig

   Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland

   Contribution

   BL, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

7. Ari Waisman

   Institute for Molecular Medicine, University Medical Center, Johannes-Gutenberg University of Mainz, Mainz, Germany

   Contribution

   AW, Conception and design, Drafting or revising the article, Contributed unpublished essential data or reagents

   Contributed equally with

   Burkhard Becher

   Competing interests

   The authors declare that no competing interests exist.

8. Burkhard Becher

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

   Contribution

   BB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Ari Waisman

   For correspondence

   becher@immunology.uzh.ch

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-1541-7867

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