In both humans and mice, CD4+ T cells reactive to self-derived antigens have been implicated in a range of autoinflammatory processes. To promote disease, such cells must evade tolerogenic mechanisms in the thymus and in secondary lymphoid organs. However, the factors that render self-reactive CD4+ Foxp3neg conventional (Tconv) cells prone to regulation remain incompletely understood. Moreover, it is unclear whether these same factors govern the pathogenic potential of self-reactive CD4+ Tconv cells. Previous work on this topic has focused on the sensitivity with which a CD4+ T cell recognizes and responds to a given peptide-MHC class II (pMHC-II) ligand. Yet, to assess the impact of varying T cell sensitivities, many studies have relied on the analysis of T cells reactive to foreign model antigens; immune responses towards such antigens may not recapitulate those targeting bona fide self-antigens. Using T cell receptor (TCR) profiling paired with in vivo clonal analysis of T cell differentiation, we characterized two panels of naturally occurring CD4+ Tconv cell clones reactive to endogenous self-ligands. The first consisted of self-reactive CD4+ Tconv cell clones that infiltrate the prostate following systemic Treg cell ablation. A subset of these clones were highly proliferative in the lymphoid organs at steady state and exhibited overt reactivity to self-ligands displayed by dendritic cells (DCs), yet were not purged by clonal deletion. These clones spontaneously adopted numerous hallmarks of T follicular helper (Tfh) cells, including expression of Bcl6 and PD-1. yet failed to produce common effector cytokines at baseline. The second panel of naturally occurring CD4+ Tconv cell clones consisted of TCRs reactive to a known tissue-specific antigen (TSA), Tcaf3646-658 (termed “C4” peptide). Analysis of these clones revealed preferential thymic Foxp3+ regulatory T (Treg) cell differentiation among clones exhibiting higher sensitivities to C4/I-Ab. Notably, less sensitive C4-reactive clones retained the ability to infiltrate the prostate in various inflammatory contexts, including infection, systemic Treg cell ablation, and oncogene-driven prostate tumors. Collectively, our work identifies two distinct self-reactive CD4+ Tconv cell populations kept in check by Treg cells at steady state: one that interacts with both DCs and B cells by adopting a Tfh-like phenotype, and one that senses TSAs but remains phenotypically naïve until released from mechanisms of peripheral T cell tolerance. Future work will elucidate how the interplay between these populations shapes autoimmune and antitumor responses.