Asymmetric integrin segregation regulates CD8+ T cell fate during cell division

Abstract

Abstract Recent evidence suggests lineage commitment of effector and memory T cells occurs as early as the first T cell division, using the evolutionarily conserved mechanism of asymmetric cell division. In addition, successful activation of the adaptive immune response requires precise cellular localization of divided T cells in critical lymphoid niches. Although protein inheritance of asymmetrically divided T cells has been characterized and leads to two differentially fated daughter T cells, little is known about how asymmetric cell division regulates T cell migration in the lymph node and how it controls T cell differentiation. We demonstrated distinct migration and T-APC conjugation patterns and localization after the first T cell division both in vitro and in vivo. Expression of the integrin LFA-1 was the only relevant surface change during division. Using our newly generated CD11a-mYFP knock-in mice, we discovered naïve T cells reserve an intracellular store of LFA-1 located in the uropod during T cell migration. Intracellular LFA-1 quickly translocated in a Rab27-dependent manner to the cell surface within minutes of contact with antigenic stimulus. Importantly, the redistribution of both surface and intracellular LFA-1 led to a molecular asymmetry that was maintained during cell division, giving rise to daughter cells with distinct fates. We hypothesize the redistribution and asymmetric segregation of intracellular LFA-1 controls subsequent T cell encounters, localization, and cell fate.