Expression of CD103 facilitates localization and activation of CD4+ T cells within Mycobacterium tuberculosis lung-lesions

The spatial localization of CD4⁺ T cells within the Mycobacterium tuberculosis (Mtb)-infected lung is critical for optimal immunity. Here, we investigate the role of two E-cadherin binding receptors, CD103 and KLRG1. We demonstrate that KLRG1 restricts CD4⁺ T cells to the lung vasculature early during infection, and limits lesion homing at chronic stages. Subunit vaccination diminishes KLRG1 expression and increases CD103⁺ CD4⁺ T cells associated with improved bacterial control. We identify a link between CD103 expression and Th17 differentiation, as vaccine-induced Th17 cells display increased propensity to upregulate CD103 in the lung. Mixed bone marrow chimeras reveal that CD103 promotes tissue retention and localization of CD4⁺ T cells in close proximity to Mtb, facilitating enhanced TCR signaling. In contrast, CD103-deficient cells remain confined to the lesion periphery with decreased TCR activation. These findings highlight the importance of CD103 in CD4⁺ T cell localization and antigen-sensing with implications for vaccine design.