Differential requirement of kindlin-3 for T cell progenitor homing to the non-vascularized and vascularized thymus

Abstract

The role of integrin-mediated adhesion during T cell progenitor homing to and differentiation within the thymus is ill-defined, mainly due to functional overlap. To circumvent compensation, we disrupted the hematopoietic integrin regulator kindlin-3 in mice and found a progressive thymus atrophy that is primarily caused by an impaired homing capacity of T cell progenitors to the vascularized thymus. Notably, the low shear flow conditions in the vascular system at midgestation allow kindlin-3-deficient fetal liver-derived T cell progenitors to extravasate via pharyngeal vessels and colonize the avascular thymus primordium. Once in the thymus, kindlin-3 promotes intrathymic T cell proliferation by facilitating the integrin-dependent crosstalk with thymic antigen presenting cells, while intrathymic T cell migration, maturation into single positive CD4 and CD8 T cells and release into the circulation proceed without kindlin-3. Thus, kindlin-3 is dispensable for integrin-mediated T cell progenitor adhesion and signalling at low and indispensable at high shear forces.

Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

“…Talin has long been known to be indispensable for leukocyte trafficking (31–34). More recently, also kindlin-3 and its interaction with the beta2-integrin tail has been shown to be vital for neutrophil and effector T cell firm adhesion under shear flow and for neutrophil and T cell trafficking in vivo (35–38), and for homing of progenitor T cells to the vascularized thymus (39). However, talin and kindlin-3 regulate different aspects of leukocyte trafficking.…”

Activation and suppression of hematopoietic integrins in hemostasis and immunity

“…25 Finally, T-cell progenitor homing to the thymus requires kindlin-3 in postnatal or adult animals, but not during development when the thymus is still avascular. 29 The model emerging from these data is that kindlin-3 is dispensable under low shear stress or when excess ligand is available, whereas talin-1 and kindlin-3 are both required under high shear stress or ligand-limiting conditions. A possible explanation for these results is provided by observations that talin-1 alone can induce the bent-to-extended change in integrin conformation, which leads to the largest increase in affinity, whereas kindlin-3 is only required for the headpiece opening and, therefore, only modestly enhances the affinity.…”

MST1/2 Balance Immune Activation and Tolerance by Orchestrating Adhesion, Transcription, and Organelle Dynamics in Lymphocytes

“…The chemokine receptors CCR7/CCR9, as well as integrins LFA-1/VLA-4 and their counter-receptors ICAM-1/VCAM-1, are required for efficient entry of T cell progenitors into the thymus (27,28). In support, the integrin coactivator Kindlin-3 is required for T cell progenitor homing (29). Similar to MST1/MST2-deficient HSC, MST1/2 double deficient T cell progenitors have defects in migration into the thymus (26), suggesting that MST1/2 play a role in regulating integrins during this process.…”