The appendix is a secondary lymphoid organ that sits at the junction between the small and large intestine. Housing both dense lymphoid tissue and its own microbiome, it is uniquely poised to play a role in gut immune homeostasis, yet it is largely ignored. The purpose of this work was to investigate the appendiceal immune compartment across states of inflammation and to begin to interrogate the antigen reactivity of lymphocytes residing in the appendix that may contribute to various pathologies. The first portion of this thesis profiles lymphocyte phenotypes and receptor repertoires in appendicitis to try and understand if they contribute to appendicitis. Through spatial transcriptomics and single-cell sequencing, IgG-secreting plasma cells were found to be increasingly activated in appendicitis compared to controls and had greater mutational burden than other plasma cell subsets. These plasma cells are likely generated through a T cell-dependent process, via CD4+ T follicular helper cells. This study proposes the dysbiotic appendiceal microbiome during appendicitis as a source of antigen and used metagenomic sequencing and computational prediction methods to identify possible MHC II restricted bacterial peptides that could be recognized by CD4+ T cells. The remaining results described in this thesis focused on the relationship between the appendix and inflammatory bowel diseases. There is a long-standing epidemiological observation that appendectomy yields a reduced risk of ulcerative colitis, although this relationship does not exist for other intestinal pathologies such as Crohn’s disease or colorectal cancer. Due to the known contribution of T cells in colitis and prior observations of T cell activation in the appendix of inflammatory bowel disease patients, the main hypothesis of this study was that the appendix was a site containing unique colitogenic T cells that were able to contribute to disease pathology in the colon. While T cells largely lacked evidence of antigenic drive in appendicitis, CD8+ T cells had marked clonal expansion in the appendix of ulcerative colitis patients, with a subset of these cells predicted to be reactive to viral antigen. These viral-reactive CD8+ T cells in ulcerative colitis increasingly took on a terminal effector phenotype suggestive of prior antigenic stimulation in blood compared to healthy controls and were enriched in GZMK-expressing scRNA-seq clusters. Immunofluorescence staining showed granzyme K positive CD8+ T cells were increased in the colon of ulcerative colitis patients with intact appendices compared to patients who had undergone prior appendectomy, and epithelial cells from intact patients showed increased inflammatory gene expression by spatial transcriptomics. Overall, this project provides an in-depth report of the appendiceal lymphocyte populations, with a particular focus on T cell phenotypes and antigen reactivity, and beings to provide some mechanistic insight behind the observed association between the appendix and ulcerative colitis development.