Mohit Upadhye successfully defended his Ph.D. dissertation on March 27, 2025, completing the Experimental Pathology graduate program in Dr. Nitin Karandikar’s lab at the University of Iowa. His dissertation, titled “myelin-reactive CD8+ T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis (EAE),” uncovers a novel immunoregulatory role for CD8+ T cells in the context of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS).

While CD4+ T cells—particularly Th1 and Th17 subsets—are well-established mediators of MS pathogenesis, the role of CD8+ T cells has remained poorly understood. Mohit’s work revealed that adoptively transferred myelin-reactive CD8+ T cells (PLP-CD8) suppress disease in the recipient mice by modulating the phenotype and functions of splenic conventional dendritic cells (cDCs), which are key antigen-presenting cells that orchestrate adaptive T cell responses.

Within the cDC compartment, cDC1s are known to promote Th1 differentiation and cross-present antigens to CD8+ T cells, whereas cDC2s drive Th2 and Th17 polarization through antigen presentation to naïve CD4+ T cells. Mohit’s in vivo and in vitro studies demonstrated that PLP-CD8s promote both cDC1 and cDC2 subsets to adopt a mature, yet regulatory phenotype characterized by upregulation of both costimulatory and inhibitory molecules, an anti-inflammatory cytokine profile, and a reduced ability to support CD4+ T cell proliferation.

Further mechanistic dissection revealed that PLP-CD8s directly interact with cDC1s, while modulating cDC2s through paracrine signaling. Notably, direct contact with PLP-CD8 reduced MHC-II and PD-L2 expression on cDC2s, whereas exposure to supernatants from these interactions promoted a mature, regulatory phenotype—highlighting a contact-dependent suppressive effect on cDC2s.

Using single-cell RNA sequencing, Mohit identified upregulation of key immunoregulatory genes—including Cd274 (PD-L1), Cd83, Mtor, Tgfb1 (TGF-β1), and Foxo3—primarily within the cDC2 subset, but also present in cDC1. Pathway enrichment analysis revealed robust activation of immunoregulatory KEGG pathways, reinforcing a tolerogenic shift in dendritic cell function in response to PLP-CD8 interaction.

In summary, Mohit’s dissertation defines a novel mechanism by which myelin-reactive CD8+ T cells induced mature and regulatory changes in cDC subsets to suppress CD4+ T cell responses and mitigate EAE pathogenesis. His findings offer new insights into the immunoregulatory circuitry in MS and suggest potential avenues for therapeutic intervention. This work was recently published in the Journal of Neuroinflammation (https://doi.org/10.1186/s12974-025-03377-8).

In addition to Dr. Karandikar, Drs. John Harty, Ashutosh Mangalam, Ali Jabbari, and Scott Lieberman served on Mohit’s dissertation committee.