The innate immune system provides a crucial first line of defense against invading pathogens, and in addition, activates and guides subsequent adaptive immune responses. Although the role of innate immunity in promoting adaptive immunity has long been appreciated (Janeway, 1989), most studies have focused on the contributions of Toll-like receptors (TLRs), and significantly less is known about how other innate immune pathways influence the adaptive immune system (McDaniel et al., 2021).

Inflammasomes are a heterogeneous group of cytosolic innate immune sensors, each of which initiates signaling in response to specific stimuli, including pathogen-associated molecules and activities or cellular damage (Awad et al., 2018; Downs et al., 2020; Palazon-Riquelme and Lopez-Castejon, 2018). Regardless of the input signal, a common output of inflammasome activation is the recruitment and activation of caspase proteases (e.g., Caspase-1), which cleave and activate the inflammatory cytokines pro-interleukin (IL)-1β and pro-IL-18 and/or the pore-forming protein gasdermin D. Active gasdermin D oligomerizes in the plasma membrane to form pores that serve as a conduit for the release of active IL-1β and IL-18. Active gasdermin D can also initiate pyroptotic cell death and/or lysis (de Vasconcelos et al., 2019; DiPeso et al., 2017; Evavold et al., 2018; He et al., 2015; Heilig et al., 2018; Kayagaki et al., 2015; Shi et al., 2015). In intestinal epithelial cells (IECs), inflammasome activation also results in the expulsion of cells from the epithelial monolayer into the intestinal lumen. Pyroptosis and cell expulsion provide host defense against intracellular pathogens by eliminating their replicative niche (Fattinger et al., 2021; Hausmann et al., 2020; Mitchell et al., 2020; Rauch et al., 2017; Sellin et al., 2014).

The role of inflammasome activation during adaptive immunity remains incompletely understood, and inflammasomes appear to have both beneficial and detrimental effects on the adaptive response, depending on the context (Deets and Vance, 2021; Evavold and Kagan, 2018). In addition, most studies to date use whole-animal knockouts and intravenous infection models, making it difficult to draw conclusions about the effects of inflammasome activation within different cell types. While there remains limited evidence on how inflammasome activation and pyroptosis of either hematopoietic cells or IECs impacts presentation of cell-derived antigens, systemic IL-1β and IL-18 have been implicated in driving type one helper T cell (Th1), Th17, and CD8⁺ T cell immunity following bacterial infections (Kupz et al., 2012; O’Donnell et al., 2014; Pham et al., 2017; Tourlomousis et al., 2020; Trunk and Oxenius, 2012). Likewise, CD4⁺ and CD8⁺ T cell responses to influenza have been shown to require inflammasome signaling components, presumably in lung macrophages (Ichinohe et al., 2009). However, inflammasome activation has also been found to inhibit T cell-mediated immunity (Sauer et al., 2011; Theisen and Sauer, 2017), including through the pyroptotic destruction of key antigen presenting cells (APCs) (McDaniel et al., 2020; Tourlomousis et al., 2020). Inflammasomes have also been suggested to influence adaptive responses to tumors (reviewed in Deets and Vance, 2021; Evavold and Kagan, 2018).

Most studies to date have evaluated the effects of inflammasome activation on adaptive immunity in the context of infections. Though physiologically relevant, microbial infections are also complex to analyze since they engage multiple innate receptors, including TLRs. It thus remains unknown whether inflammasome activation alone provides sufficient co-stimulatory signals to initiate an adaptive response, and if so, which inflammasome-containing cell populations can drive this response. In addition, the fate of antigens after inflammasome activation remains poorly understood. Conceivably, expulsion of pyroptotic epithelial cells may result in the loss of antigen, thereby hindering adaptive immunity, or alternatively, pyroptosis may promote the release of epithelial or hematopoietic cell antigens to APCs to activate adaptive immunity.

To investigate how inflammasome activation might influence adaptive immunity, we focused on the NAIP–NLRC4 inflammasomes, which specifically respond to flagellin (via NAIP5/6) or bacterial type III secretion system proteins (via NAIP1/2) (Kofoed and Vance, 2011; Rauch et al., 2016; Zhao et al., 2016; Zhao et al., 2011). Although most inflammasomes require the adaptor protein Apoptosis-associated Speck-like protein containing a Caspase activation and recruitment domain (ASC) to recruit and activate pro-Caspase-1, NLRC4 is able to bind and activate pro-Caspase-1 directly—though ASC (encoded by the Pycard gene) has been found to enhance the production of IL-1β and IL-18 (Broz et al., 2010a; Broz et al., 2010b; Mariathasan et al., 2004). Cleavage of gasdermin D does not require ASC following NAIP–NLRC4 activation (He et al., 2015; Kayagaki et al., 2015; Shi et al., 2015). NAIPs and NLRC4 are highly expressed in IECs, where they provide defense against enteric bacterial pathogens including Citrobacter (Nordlander et al., 2014), Salmonella (Fattinger et al., 2021; Hausmann et al., 2020; Rauch et al., 2017; Sellin et al., 2014), and Shigella (Mitchell et al., 2020). Inflammasome-driven IEC expulsion appears to be a major mechanism by which NAIP–NLRC4 provides innate defense against enteric pathogens. However, it is not currently known how pyroptosis and IEC expulsion influence the availability of IEC-derived antigens and what impact this has on the adaptive immune response.

Indeed, even at steady state in the absence of inflammasome activation and pyroptosis, it remains unclear how antigens present in IECs are delivered to APCs to stimulate adaptive immune responses, or whether perhaps IECs can directly activate T cells (Chulkina et al., 2020; Heuberger et al., 2021; Liu and Lefrançois, 2004; Nakazawa et al., 2004). Conventional type one dendritic cells (cDC1s) are thought to acquire apoptotic bodies from IECs and shuttle the cell-associated antigens through the MHC II pathway to drive a tolerogenic CD4⁺ T cell response under homeostatic conditions (Cummings et al., 2016; Huang et al., 2000). cDC1s were also recently shown to induce Foxp3⁺CD8⁺ T_regs through the cross-presentation of IEC-derived tissue-specific antigens (Joeris et al., 2021). Additionally, in the context of inflammation, a subset of migratory cDC1s have been shown to also take up IEC-derived antigen to activate CD8⁺ T cells; however, it remains unclear how these cDC1s acquire IEC-derived antigen.

Because NAIP–NLRC4 activation can result in IEC pyroptosis prior to the expulsion of IECs from the epithelium (Rauch et al., 2017), we hypothesized that cell lysis could release antigen basolaterally, which could then be taken up by cDC1s and cross-presented to CD8⁺ T cells. To address the role of inflammasome-induced cell death in antigen presentation and subsequent activation of CD8⁺ T cells, we used a genetic mouse model in which an ovalbumin (Ova)-flagellin (Fla) fusion protein is inducibly expressed specifically in IECs (Nichols et al., 2017b). The OvaFla fusion protein provides a model antigenic epitope (SIINFEKL) to activate specific CD8⁺ (OT-I) T cells (Hogquist et al., 1994), concomitant with the activation of the NAIP–NLRC4 inflammasome by a C-terminal fragment of flagellin that does not activate TLR5. This genetic system has the advantage of selectively activating inflammasome responses in the absence of exogenous or pathogen-derived TLR ligands, allowing us to address the sufficiency of inflammasome activation for adaptive responses. Our results suggest the existence of distinct NLRC4-dependent and NLRC4-independent pathways for cross-presentation of IEC-derived antigens in vivo.

IECs represent an important barrier surface that protects against enteric pathogens. At the same time, IECs also represent a potential replicative niche for pathogens. As such, the immune system must survey IECs for foreign antigens and present those antigens to activate protective adaptive immune responses. In general, it remains poorly understood whether and how IEC-derived antigens are presented to activate T cell responses. In particular, the relative contributions of direct versus cross-presentation of IEC antigens to CD8⁺ T cells have not been thoroughly investigated. Here, we employed a genetic system that inducibly expresses a model antigen (ovalbumin) fused to an NAIP–NLRC4 agonist (flagellin) within the cytosol of cells (Nichols et al., 2017b). We crossed these ‘OvaFla’ mice to Villin-Cre-ER^T2 mice, allowing for tamoxifen-inducible expression specifically in IECs. By additionally crossing to an H-2K^bm1 background (Nikolić-Zugić and Bevan, 1990; Schulze et al., 1983), and using the resulting mice as irradiated recipients for WT K^b hematopoietic donor cells, we engineered a system in which an IEC-derived ovalbumin antigen (SIINFEKL) cannot be directly presented to OT-I T cells but can still be acquired by hematopoietic cells and cross-presented. Using this system, we established in vivo that there is an antigen presentation pathway in which IEC-derived antigens are cross-presented to activate CD8⁺ T cells. This finding extends previous work indicating that ex vivo isolated DCs can cross-present IEC-derived antigens to CD8⁺ T cells (Cerovic et al., 2015; Cummings et al., 2016). We show that these antigens can activate antigen-specific CD8⁺ T cells in vivo, and that this activation can occur even when direct presentation is genetically eliminated. We suggest that the cross-presentation pathway revealed by our analyses could be of importance during infection with pathogens that replicate in IECs, though future studies will be required to evaluate this hypothesis.

Our genetic system also allowed us to assess the contribution of IEC inflammasome activation to the adaptive immune response. Inflammasomes are a critical component of the innate immune response to many pathogens, and their activation is known to influence adaptive immunity (Deets and Vance, 2021). However, in previous studies, it has been difficult to isolate the specific effects of inflammasome activation on adaptive immunity because microbial pathogens activate numerous innate immune signaling pathways over the course of an infection. By providing a genetically encoded antigen and inflammasome stimulus, we were able to overcome this issue and specifically address the role of inflammasomes in adaptive CD8⁺ T cell responses in vivo. We crossed our OvaFla Villin-Cre-ER^T2 mice to mice deficient in key inflammasome components. Consistent with previous work, we found that Nlrc4^–/– mice entirely lack the inflammasome response to cytosolic flagellin, whereas Pycard^–/– mice are defective for IL-18 release but not pyroptotic cell death or IEC expulsion (Rauch et al., 2017; Figures 1C, E, 2B). We also crossed OvaFla Villin-Cre-ER^T2 mice to pyroptosis-deficient Gsdmd^–/– mice and found that they were defective for IL-18 release in vivo (Figure 1C and E).

Because Nlrc4^–/– IECs fail to undergo pyroptosis or IEC expulsion (Rauch et al., 2017), we noted that cells expressing the OvaFla transgene accumulate to much higher levels in the Nlrc4^–/– mice than in WT, Pycard^–/–, or Gsdmd^–/– mice, in which IEC expulsion still occurs (Figure 2). Higher levels of Ova antigen in IECs has previously found to correlate with higher levels of OT-I expansion in the spleen and mesenteric lymph nodes of mice (Vezys et al., 2000). Because of the differences in antigen level, comparisons of Nlrc4^–/– mice to the other genotypes must be made with caution. Nevertheless, we found that OT-I T cells in the Nlrc4^–/– OvaFla mice divide and are activated at similar levels to the WT OvaFla mice following tamoxifen administration (Figure 3B–D). This activation occurred even when direct presentation of the OT-I peptide by IECs was eliminated on the K^bm1 background (Figure 4B–C). These results are surprising for two reasons. First, it is not clear how IEC-derived antigens would be delivered to APCs in the absence of inflammasome-induced cell death. Other studies have suggested that IEC apoptosis, which may occur during homeostatic IEC turnover (Bullen et al., 2006; Hall et al., 1994; Marshman et al., 2001; Shibahara et al., 1995; Watson et al., 2005), can be a source of antigen for T cell activation (Cummings et al., 2016; Huang et al., 2000). However, apoptotic IECs are expelled apically into the intestinal lumen (Bullen et al., 2006; Hall et al., 1994; Marshman et al., 2001; Shibahara et al., 1995; Watson et al., 2005), and so the exact mechanism of basolateral antigen delivery remains unclear—though it may involve luminal sampling by intestinal phagocytes (Farache et al., 2013) and/or the transfer of plasma membrane components (trogocytosis) (Dance, 2019). Cummings et al. suggested that IECs can be engulfed by APCs, resulting in antigen presentation on MHC class II to induce CD4⁺ T regulatory cells, but this work did not examine antigen-specific responses or MHC class I presentation to CD8⁺ T cells. Additionally, Joeris et al. recently showed that cDC1s can present IEC-derived self-antigen to drive cross-tolerant OT-I T cells (Joeris et al., 2021). Further work is therefore needed to understand mechanisms of IEC-derived antigen presentation in the absence of inflammatory cell death. The second reason we were surprised to see CD8⁺ T cell activation in Nlrc4^–/– OvaFla mice is that these mice are presumably unable to produce inflammatory signals necessary to induce APC activation. However, previous studies have shown that OT-I T cells can be activated from constitutively expressed Ova in the absence of inflammation. In this scenario, the CD8⁺ T cells go on to become anergic and are likely eventually deleted from the periphery (Kurts et al., 1996; Kurts et al., 1997; Liu et al., 2007; Vezys et al., 2000).

Since WT, Pycard^–/–, and Gsdmd^–/– IECs all undergo cell death and IEC expulsion in response to NLRC4 activation, these mice exhibit similar levels of OvaFla transgene expression in IECs, allowing for comparisons between these mouse strains (Figure 2C). We found that OvaFla production leads to CD8⁺ T cell expansion and activation in all of these strains. The expansion is at least partially dependent on gasdermin D, as Gsdmd^–/– OvaFla mice have significantly fewer OT-I T cells than their WT counterparts (Figure 3B and C). Interestingly, ASC-deficient OvaFla mice—in which IECs still undergo pyroptosis following NAIP–NLRC4 activation (Rauch et al., 2016)—show similar, or even increased, OT-I numbers in their tissues relative to WT OvaFla mice (Figure 3B and C). These data, combined with the fact that Gsdmd^–/– and Pycard^–/– OvaFla mice have little to no detectable IL-18 in their serum (Figure 1C and E), suggest that the difference in OT-I T cell proliferation between these strains is in some way related to pyroptotic antigen release. One hypothesis is that the gasdermin D pore, which has been shown to provide a lysis-independent portal for IL-1β, IL-18, and other small proteins (DiPeso et al., 2017; Evavold et al., 2018; Heilig et al., 2018), may act as a channel for small antigens to escape IECs prior to cell expulsion.

Because Gsdmd deficiency only modestly affected OT-I responses, our data additionally suggest that there may be both GSDMD-dependent and GSDMD-independent pathways by which IEC antigens can be cross-presented to CD8⁺ T cells. Because Batf3^–/–-dependent cDC1s have a known role in cross-presenting IEC-derived antigen (Cerovic et al., 2015), we sought to determine if the cross-presentation occurring in the OvaFla mice similarly relied on these cells. We compared bm1⁺ OvaFla mice that received B6 CD45.1 bone marrow with those that received bone marrow from Batf3-deficient mice (Figure 5A). To our surprise, we found OT-I T cells were cross-primed in the bm1⁺ WT OvaFla mice, even in the recipients that lacked cDC1s (Figure 5A–D). Interestingly, these data contrast with the bm1⁺ Nlrc4^–/– OvaFla mice, where the recipients given Batf3-deficient bone marrow had significantly fewer activated OT-I T cells than their counterparts given Batf3-sufficient bone marrow. OT-I T cell activation in the bm1⁺ Gsdmd^–/– OvaFla mice partially relied on Batf3⁺ DCs. Furthermore, CellTrace Violet data show the OT-I T cells in the bm1⁺ Nlrc4^–/– and bm1⁺ Gsdmd^–/– OvaFla mice undergo fewer rounds of division in the absence of Batf3 cDC1s (Figure 5D). These data suggest there may be two possible cross-presentation pathways for IEC-derived antigen: one that occurs in the presence, and one in the absence, of inflammasome-derived inflammatory signals. We found that Zbtb46⁺ bone marrow-derived cells were required for both pathways (Figure 6), indicating that cross-presentation seen under inflammatory conditions occurs through a Batf3-independent but Zbtb46-dependent cDC population. We hypothesize that these cells are cDC2s, as recent work shows that cDC2s can take on characteristics of cDC1s under inflammatory conditions (Bosteels et al., 2020) or in the absence of Batf3 (Lukowski et al., 2021).

Our work raises several interesting questions for future study, including the mechanism of cDC maturation. The traditional model of DC maturation involves TLR signaling on the DC (Dalod et al., 2014). IL-1R (Pang et al., 2013) or IL-18R (Li et al., 2004) on these cells might also trigger maturation, though further investigation is needed to understand how IL-1β, IL-18, or other inflammatory signals, such as eicosanoids (McDougal et al., 2021; Oyesola et al., 2021; Rauch et al., 2017), downstream of inflammasome activation might drive maturation of DCs that have acquired IEC-derived antigen.

Overall, our studies show that IEC-derived antigens are cross-presented both following NAIP–NLRC4 activation and under apparent homeostatic conditions in the absence of NAIP–NLRC4-induced inflammation. In the context of NAIP–NLRC4 activation, cross-priming of CD8⁺ T cells is partially dependent on gasdermin D-mediated pyroptosis and requires a Batf3-independent cDC population. These data add insights to the complex interactions between innate and adaptive immune responses occurring in the intestine.

Immunofluorescence images have been deposited in Dryad and can be found at https://doi.org/10.6078/D1ST46. All remaining data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1-6, Figure 3-figure supplement 1, Figure 4-figure supplement 1, Figure 5-figure supplement 1, Figure 5-figure supplement 4, Figure 6-figure supplement 2.

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Author details

1. Katherine A Deets

   Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1731-1641

2. Randilea Nichols Doyle

   Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States

   Present address

   Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States

   Contribution

   Conceptualization

   Competing interests

   No competing interests declared

3. Isabella Rauch

   Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, United States

   Contribution

   Conceptualization, Writing – review and editing

   Competing interests

   No competing interests declared

4. Russell E Vance

   1. Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
   2. Cancer Research Laboratory, University of California, Berkeley, Berkeley, United States
   3. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States

   Contribution

   Conceptualization, Funding acquisition, Resources, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   rvance@berkeley.edu

   Competing interests

   consults for Ventus Therapeutics and Tempest Therapeutics and is a Reviewing Editor for eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-6686-3912

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