The innate immune system detects pathogens and initiates adaptive immune responses. Inflammasomes are central components of the innate immune system, but whether inflammasomes provide sufficient signals to activate adaptive immunity is unclear. In this dissertation, I present the work I have done using a genetic mouse model system that allowed me to simultaneously express the model antigen ovalbumin (Ova) and activate the NAIP–NLRC4 inflammasome in specific cells throughout the mouse. Chapter One begins with an introduction to innate and adaptive immunity. I then provide an overview of inflammasome activation, followed by a discussion of what is currently known about how inflammasomes influence adaptive immunity. This section discusses the roles inflammasome-driven lytic cell death (termed pyroptosis) might play in antigen release, evidence for inflammasome activation driving CD4+ and CD8+ T cell responses, and instances where inflammasome activation appears to inhibit adaptive immunity. This chapter closes with evidence for inflammasomes influencing adaptive immunity in vaccines, anti-tumor immunity, and autoimmunity. Overall, Chapter One provides a foundation for appreciating why we need better understanding of the role inflammasome activation plays in driving adaptive immune responses. In Chapter Two, I present my early doctoral work, where I began to explore what role(s) NAIP–NLRC4 inflammasome activation might have on adaptive T cell immunity. Here I introduce the OvaFla mouse model previously, which was described by the Vance lab. These mice use the Cre-Lox system to inducibly express a fusion protein containing Ova antigen and the 166 amino acid C-terminal of flagellin, which will activate NAIP–NLRC4 but not an alternative flagellin sensor called TLR5. For experiments in this chapter, I crossed these “OvaFla” mice with mice containing a tamoxifen-inducible Cre driver, Cre-ERT2, that results in systemic OvaFla expression following tamoxifen administration. I found that systemic OvaFla can drive cross priming of CD8+ T cells in both WT and NLRC4-deficient mice. However, because Cre-ERT2 is expressed throughout the mouse, we remain unsure where and how this cross priming is occurring. I did determine, however, that signaling through the IL-18R on cross presenting cells is not required for CD8+ T cell activation. One potential benefit to the OvaFla Cre-ERT2 system is that localized tamoxifen application can be used to drive a more focused Cre expression. Additionally, bone marrow-derived cells from these mice retain the ability to activate OvaFla, which may be useful for future in vitro studies. In all, the work presented in this chapter provides some initial insights into the OvaFla Cre-ERT2 system, with suggestions on how they may be a useful tool for others. Chapter Three describes the bulk of my doctoral work, which specifically focused on activation of the NAIP–NLRC4 inflammasome in intestinal epithelial cells (IECs). NAIP–NLRC4 activation in these cells results in IEC pyroptosis, followed by an expulsion of the IEC into the intestinal lumen. One of my original hypotheses was that pyroptosis, which is mediated by the pore-forming protein Gasdermin D, provides an opportunity for cytosolic antigen to escape into the underlying lamina propria. In the lamina propria, the antigen is theoretically available to be cross-presented on dendritic cells (DCs), which can then drive antigen-specific CD8+ T cell activation. To test this hypothesis, I crossed the OvaFla mice with the Villin-Cre-ERT2 mice, thereby creating animals where tamoxifen administration results in robust OvaFla expression in IECs. These OvaFla Villin-Cre-ERT2 mice were crossed onto Gasdermin D-, ASC-, and NLRC4-deficient backgrounds. In support of my hypothesis, my work showed that IEC-derived antigens can be cross presented to CD8+ T cells in vivo, but we were surprised to find that this cross presentation occurred in both WT and NLRC4-deficient OvaFla mice. Additionally, Gasdermin D-mediated pyroptosis played only a partial role in CD8+ T cell cross-priming. My project then shifted to understanding whether there were any mechanistic differences in antigen cross-presentation between inflammatory conditions (NLRC4-dependent) and steady state (NLRC4-independent). By using two separate genetic knockout mouse lines, I found that cross presentation of IEC antigens during non-inflammatory conditions (in NLRC4-deficient mice) relies on a subset of classical DCs (cDCs) that require the Batf3 transcription factor (cDC1s)—these findings align with previously published data. However, in the presence of inflammasome activation, a Batf3-independent cDC population (likely cDC2s) can cross present IEC-derived antigen. Altogether, these data provide a better understanding of the complex interactions between IECs, DCs, and CD8+ T cells in the gut. In Chapter Four, I close my dissertation with a discussion on some of the remaining questions generated from my work. These questions center around the mechanism(s) of antigen acquisition functional maturation of the cross presenting cDCs. In all, my dissertation work has provided a stripped-down approach to understanding how inflammasome activation influences adaptive immunity. Unlike previous studies that rely on infection models, the OvaFla system allowed me to selectively activate the NAIP–NLRC4 inflammasome and uncover a Batf3+ cDC1-independent pathway of IEC antigen cross presentation.