Contrasting roles for IKK-regulated inflammatory signalling pathways for development and maintenance of type 1 and adaptive γδ T cells

The NF-κB family of transcription factors plays critical roles in controlling development and function of many cell types (Bonizzi and Karin, 2004). Canonical NF-κB signalling is mediated by hetero- or homodimers of p50, RELA, and cREL family members that are sequestered in the cytoplasm by inhibitory proteins, the inhibitors of kappa B (IκB) family and the related protein NFκB1. The key regulator of NF-κB dimer release is the inhibitor of kappa-B kinase (IKK) complex, a trimeric complex of two kinases, IKK1 (IKKα) and IKK2 (IKKβ), and a third regulatory component, NEMO (IKKγ). IKK phosphorylates IκB proteins, targeting them for degradation by the proteasome and releasing NF-κB dimers to enter the nucleus.

In αβ T cells, activation of NF-κB is a well-recognised critical early event during T cell receptor antigen recognition (Gerondakis and Siebenlist, 2010). In the absence of REL subunits, or upstream NF-κB activators, such as TAK1 or IKK complex, T cells fail to blast transform or enter cell cycle (Webb et al., 2019; Xing et al., 2016). Consequently, mice with T cell-specific ablation of RELA and/or cREL have peripheral naive T cells, but lack effector or memory phenotype T cells (Webb et al., 2019; Zheng et al., 2003). As well as regulating activation, the NF-κB signalling pathway also has important functions in the development and survival of αβ T cells. While activation of NF-κB by TCR appears redundant for normal selection of thymocytes during thymic development (Schmidt-Supprian et al., 2004; Webb et al., 2019), signals from TNF and other TNF receptor superfamily members (TNFRSF) are important for survival and differentiation of post-selection single positive thymocytes. NF-κB is required for re-expression of Il7r following thymic development, that is necessary for long-term IL-7 dependent survival of peripheral naive T cells (Miller et al., 2014; Silva et al., 2014). Additionally, long-term survival of fully mature naive CD4⁺ T cells is dependent upon tonic NF-κB since CD4^CreERT-induced deletion of REL subunits results in a substantial loss of T cells (Carty et al., 2023).

In addition to activating NF-κB dependent transcriptional activity to regulate T cell survival, TNF-induced NF-κB signalling pathways also control cell death through the activity of IKK. In addition to its function as an IKK, the IKK complex also directly controls cell survival independent of NF-κB activation. While thymic development is largely normal in the absence of REL subunits (Webb et al., 2019), IKK deficiency in αβ T cells results in a profound block in thymic development that is arrested at the SP stage (Schmidt-Supprian et al., 2003) due to TNF-induced apoptosis (Webb et al., 2016). Ligation of TNFR1 causes recruitment of TRADD, TRAF2, and the serine/threonine kinase RIPK1. The ubiquitin ligases TRAF2, cellular inhibitor of apoptosis proteins (cIAPs), and the linear ubiquitin chain assembly complex (LUBAC), add ubiquitin chain modifications to themselves and RIPK1, creating a scaffold that allows recruitment and activation of the TAB/TAK and IKK complexes that in turn activate NF-κB. This is termed complex I (Annibaldi and Meier, 2018; Vandenabeele et al., 2010). A failure to maintain the stability of this complex results in the formation of cell death inducing complexes composed of TRADD, FADD, CASPASE8, and RIPK1 that induce apoptosis, a function dependent upon RIPK1 kinase activity (Annibaldi and Meier, 2018; Dondelinger et al., 2016; Ting and Bertrand, 2016). Phosphorylation of RIPK1 by IKK blocks RIPK1 kinase activity and therefore its capacity to induce apoptosis (Dondelinger et al., 2015). In thymocytes, it is this function of IKK, and not NF-κB activation, that is critical for their survival and onward development and accounts for the phenotype observed in IKK deficiency (Blanchett et al., 2022; Webb et al., 2019). Survival of mature T cells depends upon both the IKK capacity to repress RIPK1 and its function to activate NF-κB (Carty et al., 2023). RIPK1-dependent cell death of thymocytes and mature naive T cells is mediated by apoptosis, rather than necroptosis, since cell death is CASPASE8 dependent (Carty et al., 2023). Thymocytes are not susceptible to necroptosis as they lack expression of MLKL (Webb et al., 2019), a key effector molecule for mediating necroptotic cell death. Similarly, resting peripheral αβ T cells are resistant to necroptotic cell death, since Casp8 deletion has little impact on peripheral αβ T cell compartments (Ch’en et al., 2008; Ch’en et al., 2011). In contrast, activated T cells are acutely susceptible to necroptosis and readily undergo necroptotic cell death in the absence of Casp8 expression during LCMV infection or following activation in vitro (Ch’en et al., 2008; Ch’en et al., 2011).

γδ T cells are a distinct subset of T lymphocytes that play a unique and versatile role in host immunity. While conventional αβ T cells rely on MHC-restricted antigen presentation, γδ T cells recognise stress-induced ligands, phosphoantigens, and non-peptidic molecules directly (Deseke and Prinz, 2020). Distinct subsets of innate-like γδ T cells develop with specific effector functions, such as type 1 and 17 γδ T cells (Muñoz-Ruiz et al., 2017; Vantourout and Hayday, 2013). Weak TCR signalling during thymic development is associated with generation of type 17 γδ T cells, which are CD44^hi and lack CD27 expression, and develop as a finite wave in a very specific window of embryogenesis (Muñoz-Ruiz et al., 2017). In contrast, type 1 γδ T cell development is associated with strong TCR signalling and cells assume a CD122^hiCD27⁺ phenotype during thymic development. The remainder of γδ T cells in lymphoid tissues are undifferentiated and exhibit a more naive CD44^loCD27⁺ phenotype and are termed by some as naive or adaptive γδ T cells. The pre-differentiated type 1 and 17 states enable them to act as early responders in immune defence. As such, while it seems likely that inflammatory NF-κB and cell death signalling pathways would be important regulators of γδ T cell development and homeostasis, as is the case for αβ T cells, very little is currently known. Evidence that NF-κB signalling could be important comes from the observation that the TNFRSF member CD27 is an important regulator of type 1 γδ T cell development (Ribot et al., 2009) and is also an activator of NF-κB signalling required for survival of αβ T cells (Silva et al., 2014). However, whether and how inflammatory signalling pathways mediated by IKK and NF-κB for the normal homeostasis of γδ T cells remains unknown.

In the present study, we used mouse genetics to investigate the role of IKK and NF-κB survival and cell death pathways for homeostasis of γδ T cells. We found evidence that thymic development of type I γδ T cells was dependent on these pathways, but redundant for adaptive γδ T cells. However, long-term survival of adaptive γδ T cells was dependent upon both NF-κB and, in part, RIPK1-dependent survival pathways and both populations were highly susceptible to necroptotic cell death.

The IKK complex is a critical regulator of cell death, differentiation, and inflammation in multiple cell types, including αβ T cells. In the present study, we sought to understand whether IKK signalling was also important for the development and maintenance of γδ T cells, which are implicated as early responders in a host of different inflammatory settings. We found that IKK was critical for establishing a mature γδ T cell compartment, but found evidence for contrasting roles and mechanisms of downstream pathways for the development and maintenance of different subsets.

The inhibitor of κB kinase activity of the IKK complex is critical for activating NF-κB signalling, so we were able to demonstrate the essential role of this transcription factor by two independent means – either ablating the upstream IKK complex or direct ablation of canonical REL subunits. Numbers of type 1 γδ T cells in the thymus were substantially reduced in both settings, suggesting that generation of this pre-differentiated subset requires NF-κB signalling to support their ontogeny. In contrast, NF-κB signalling was redundant for both specification of progenitors to a γδ T cell lineage and generation of adaptive γδ T cells, as numbers of progenitors and adaptive γδ T cells were largely normal in both REL- and IKK-deficient strains. Strikingly, however, mature adaptive γδ T cells were largely absent in both REL- and IKK-deficient mice, revealing that NF-κB is critical for maintenance of mature γδ T cells. Assessing the role of different REL subunits also revealed distinct requirements for development vs maintenance that mirrored preferences observed in αβ T cells. Generation of effector αβ T cells is highly dependent upon NF-κB, since loss of cREL alone is sufficient to block development of αβ T cell memory (Webb et al., 2019; Zheng et al., 2003). Similarly, we found that loss of RELA alone was sufficient to impair development of type 1 γδ T cells, suggesting the cREL and p50 alone are insufficient for their development. Furthermore, in naive αβ T cell, there is evidence of redundancy between REL subunits. Expression of cREL and p50 in the absence of RELA is sufficient to maintain naive αβ T cells, while expression of cREL alone, in RELA/p50 double knockouts, is not (Webb et al., 2019). We also found this to be the exact case for adaptive γδ T cells. These subtly distinct requirements for NF-κB probably reflect both distinct biological processes involved, ontogeny vs maintenance, but also potentially the receptors involved in triggering signalling. TNFRSF members appear to be implicated in triggering survival signalling in naive αβ T cells (Silva et al., 2014) while generation of differentiated αβ T effectors is dependent on strong agonist triggers from TCR and also TNFRSF members (Layzell et al., 2025). This is also true of Foxp3⁺ regulatory T cells, that require both RELA and cREL for their development (Isomura et al., 2009; Messina et al., 2016), and are induced by a combination of both agonist TCR and TNFRSF signalling, amongst other receptors.

In αβ T cells, IKK also plays a crucial role in controlling cell survival directly by its repressive activity upon the cell death regulator, RIPK1. Developing thymocytes do not require NF-κB signalling for development but do become exquisitely sensitive to TNF-induced cell death in the absence of IKK (Webb et al., 2019), while mature naive T cells require IKK expression to both repress RIPK1 and activate an NF-κB dependent survival signal. The balance between control of NF-κB and blocking cell death by IKK appears different in γδ T cells, as does the control of cell death processes themselves. Neither αβ nor γδ thymocytes undergo necroptosis in the absence of CASPASE8, while, in stark contrast to resting αβ T cells, adaptive, and type 1 γδ T cells in the periphery were exquisitely sensitive to the induction of necroptosis in the absence of CASPASE8. This appears to be determined in part by expression of MLKL that is present in γδ T cells but absent from resting αβ T cells (ImmGen browser enquiry; Heng et al., 2008). Using kinase-dead RIPK1, it was possible to test the importance of regulation of RIPK1-dependent cell death pathways by IKK, since this RIPK1 mutant blocks both necroptosis and apoptosis, while CASPASE8 ablation served to block apoptosis but also redirected cell death processes to a necroptotic modality. IKKΔT^CD2 mice expressing kinase-dead RIPK1 did exhibit some significant, albeit incomplete, rescue of the peripheral T cell compartment. The phenotype of REL-ablated mice confirmed that IKK is required to trigger an NF-κB dependent survival programme. The relative importance of IKK-induced NF-κB vs IKK-mediated repression of RIPK1 for the maintenance of peripheral γδ T cells is not easy to disentangle. The extent of peripheral γδ T loss in the absence of IKK was substantially greater than observed in REL-deficient strains. Kinase-dead RIPK1 restored peripheral γδ T cell levels to similar to those observed in REL-deficient mice, suggesting that the impact of IKK deficiency is indeed a compound effect of losing both IKK-induced NF-κB activity and loss of IKK-dependent repression of RIPK1. It would be interesting to test the impact of losing IKK-dependent control of RIPK1 in the context of normal NF-κB activation upon peripheral γδ T cell compartment.

In order to target gene deletion prior to γδ T cell commitment, we employed the use of huCD2^iCre that is expressed from common lymphoid progenitors. This will inevitably also target deletion in αβ T cells, the consequences of which have already been extensively characterised for IKK, REL and CASPASE8 genes (Islam et al., 2025; Webb et al., 2019; Webb et al., 2016). This does raise the question of whether alterations to the αβ T cell compartment affect the phenotypes we describe amongst γδ T cells. Studies of TCRα knockout mice confirm that development and maintenance of γδ T cells does not depend upon the presence of αβ T cells (Hayday and Tigelaar, 2003; Philpott et al., 1992). However, in the absence of peripheral αβ T cells, as is the case in IKKΔT^CD2 mice, there will be reduced competition for cytokines that both lineages rely upon, such as IL-7 and IL-15 (French et al., 2005). Potential alterations to homeostatic niches did not appear to impact our results, however. The loss of γδ T cells in the strains we investigated here occurred both in the presence and absence of αβ T cells. We observed normal thymic development of γδ T cells but their complete absence from peripheral compartments in both IKKΔT^CD2 and Casp8.IKKΔT^CD2 strains, in spite of the fact that development and peripheral population of αβ T cell compartment is completely blocked in IKKΔT^CD2 mice but restored in Casp8.IKKΔT^CD2 mice. Therefore, an absence of competition for IL-7 and IL-15 in IKKΔT^CD2 mice is not sufficient to overcome survival defects of γδ T cells we observed in these strains and the defects in the γδ T cell compartment do appear cell intrinsic.

Type 17 γδ T cells are primarily generated during embryonic stages of development (Muñoz-Ruiz et al., 2017), and so we could not directly observe their intrathymic generation in adult mice. As such, the presence or absence of cells in adult mice could reflect either developmental processes and/or their defective survival. Nevertheless, there were still some useful conclusions we could draw. The maintenance of the mature type 17 γδ T cells does depend on NF-κB signalling. Peripheral numbers of type 17 γδ T cells were reduced by around two-thirds in both IKK- and REL-deficient strains. However, in contrast to other subsets, there was no evidence that kinase-dead RIPK1 mediated any rescue of type 17 subset, and they did not appear to be sensitive to necroptosis in the absence of CASPASE8. Their numbers were also not restored in Casp8.IKKΔT^CD2 mice, strongly suggesting that the sole defect in IKK-deficient strains was the absence of NF-κB activation. An important caveat here is that REL and IKK-deficient strains also lack effector αβ T cell populations in the absence of NF-κB activation (Webb et al., 2019). There are reports of ‘trans-conditioning’, whereby development of type 17 γδ T cells is promoted by type 17 αβ T cells (Do et al., 2012). Therefore, it is possible that a failure of trans-conditioning by αβ type 17 T cells is a contributing factor in REL- and IKK-deficient strains. However, our findings are also consistent with other studies that show that RelA is involved in the development of type 17 γδ T cells (Powolny-Budnicka et al., 2011). The same study also implicated RelB transcription factor in the development of type 17 γδ T cells. This appears at odds with our findings of normal development of these cells in IKK1-deficient mice, since IKK1 homodimers mediate activation of the alternative NF-κB pathway. It is possible that type 17 γδ T cells are still RelB dependent in IKK1ΔT^CD2 mice but that there is redundancy between IKK subunits to activate RelB containing NF-κB dimers, permitting development of these cells. The stark contrast in sensitivity of type 17 and other subsets to necroptosis in the absence of CASPASE8 was surprising, as they all appear to express MLKL (ImmGen browser enquiry; Heng et al., 2008). It is possible this may reflect altered cell death control by the distinct fetal liver-derived progenitors from which type 17 cells are derived. Whichever the case, if confirmed, it would be of interest to identify the mechanism by which these cells are resistant to necroptosis, since they appear to express the basic elements required to form the necrosome.

In conclusion, our study reveals the complexity of regulation of inflammatory and cell death pathways in T cells of the adaptive immune system. In other cell types and tissues, IKK mediates well-defined pro-inflammatory and pro-survival functions. In contrast, in T cells, the functions of IKK and how cell death pathways are regulated vary with differentiation state and lineage. IKK-dependent repression of RIPK1 is critical for thymic development of αβ T cells, but is redundant for thymic development in γδ T cells. In common with αβ T cells, mature γδ T cells require IKK to both repress RIPK1-dependent cell death and activate NF-κB survival, with perhaps a more dominant requirement for the latter function. We found evidence that intrathymic development of type 1 γδ T cells did depend upon NF-κB. Their development is thought to be driven by strong ‘agonistic’ TCR signalling, and it is perhaps significant that other agonist-selected populations, such as NK T cells and Foxp3⁺ regulatory T cells, are also dependent upon NF-κB signalling (Isomura et al., 2009; Sivakumar et al., 2003), implying a conserved developmental mechanism governs generation of such agonist-selected populations in the thymus. It is also interesting to note that, like γδ T cells, NK T cells, and Treg are also susceptible to necroptosis in the absence of CASPASE8 expression (Islam et al., 2025; Teh et al., 2022), in contrast to resting αβ T cells, which are largely resistant. This does contrast with adaptive γδ T cells that do become exquisitely sensitive to necroptosis induction as soon as they enter the periphery. This difference may reflect the role of γδ T cells as first line early responders in immune responses, that may expose them to microbial interference of cell death pathways, that necroptosis has evolved to resist. Whichever is the case, a detailed understanding of these pathways will be critical to understand the full impact of therapies that target these potent inflammatory pathways, and that will have diverse and complex impact on adaptive immunity.

Processed cell counts are provided as supplementary source data files. Enquiries regarding access for raw flow cytometry data should be directed to the corresponding author. We will honour requests that do not conflict with our ongoing as yet unpublished studies.

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Author details

1. Farjana Islam

   Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom

   Present address

   Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8274-2021

2. Cayman Williams

   Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom

   Contribution

   Investigation, Methodology, Data curation

   Competing interests

   No competing interests declared

3. Thea Hogan

   Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom

   Contribution

   Methodology, Data curation, Visualization

   Competing interests

   No competing interests declared

4. Louise V Webb

   Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom

   Present address

   Autolus Therapeutics plc, London, United Kingdom

   Contribution

   Methodology, Data curation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0000-8862-0199

5. Ines Boal-Carvalho

   Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom

   Present address

   Virtus Respiratory Research Ltd, London, United Kingdom

   Contribution

   Formal analysis, Investigation, Supervision, Data curation, Project administration, Writing – review and editing

   For correspondence

   icarvalho@virtus-rr.com

   Competing interests

   No competing interests declared

6. Benedict Seddon

   Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing – original draft

   For correspondence

   benedict.seddon@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4352-3373

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