Inflammasome-Independent Interleukin-1 Beta Drives CD4 T Cell Effector Function and Autoimmune Inflammation

Successful generation of protective immunity is a result highly orchestrated interactions between the innate and the adaptive arms of the immune system. Innate immune cells sense the infectious threat to the host and convert it into meaningful information that is relayed to T and B cells. This relaying of information is the fundamental principle that forms the basis of all protective immune responses and is referred to as the innate control of adaptive immunity. For naïve CD4 T cell activation, innate control is exerted by the three-signal paradigm which dictates that a productive naïve CD4 T cell response requires TCR activation, co-stimulation and innate cytokine cues. The present work uncovers two consequential yet previously unknown aspects of the innate and adaptive immune, specifically dendritic cell (DC)-T cell, crosstalk. First, I found that in addition to naïve CD4 T cell activation, the three-signal paradigm continue to operate during the reactivation phase of memory CD4 T cells. Memory CD4 T cell reactivation was presumed to be independent of innate cytokine cues however, I found that signaling through interleukin (IL)-1 receptor family is required for effector cytokine production by memory CD4 T cells. Mechanistically, IL-1R signaling provides post-transcriptional stability to T cell cytokine transcripts thereby enabling productive secretion of these cytokines. Second, I discovered that DC-T cell interaction is significantly more bidirectional than previously appreciated. Innate cells such as DCs, have evolved to sense "non-self" or "altered-self" ligands via pattern recognition receptors (PRRs) and get activated only in case of pathogen invasion or tissue damage. Surprisingly, I found that autoreactive T cells can also instruct DCs to become activated independent of PRR activation. During their cognate interaction, T cell engage Tumor necrosis factor superfamily (TNFRSF) signaling in DCs to trigger innate cytokine secretion. I particularly, focused on the mechanism of IL-1β production during DC-T cell interaction as IL-1β is mediator of several autoimmune and autoinflammatory diseases. While IL-1β production is commonly attributed to inflammasome activation in autoimmune diseases, I show that that autoreactive T cells elicit IL-1β production by DCs in an inflammasome-independent manner via TNFR-Fas signaling pathway. Furthermore, this novel mechanism of IL-1β secretion drives CD4 T cell effector function, systemic leukocyte infiltration as well as autoimmune inflammation. Altogether, the findings in this dissertation provide a conceptual leap in our understanding of innate and adaptive immune cross-talk, and necessitates revisiting the established paradigm of innate signaling requirements for myeloid cell activation as well as CD4 T cell function. In addition, this work has vast implications on human health as it sheds light on the previously poorly understood mechanism of action of IL-1R blockade therapy as well as offers novel targets for therapeutic intervention of IL-1β mediated autoimmune inflammation.