Bioartificial collagen matrix limits IL-7 and IL-15-induced T-cell homeostatic proliferation without affecting T-cell receptor signaling (P1327)

Abstract

Abstract Intermittent homeostatic growth governed by STAT3/5-associated common γ chain (γc) cytokines IL-7 and IL-15 is the principal source of new T-cells after thymic involution. Lymphoproliferation, as seen in large granular lymphocyte leukemia and autoimmune lymphoproliferative syndrome (ALPS), results from failed anti-apoptotic and hyper IL-15 response. Contextual constraints in the microenvironment may also regulate homeostasis. Using primary human naïve and memory CD4+ and CD8+ T-cells, we found that bioartifical collagen matrix limits proliferation by IL-7 and IL-15, but not by anti-CD3/CD28. Flow cytometry was used to analyze collagen receptor expression on dividing T-cells. The expression of known activating collagen receptors, discoidin domain receptor (DDR)1, DDR2, and gpVI was not observed. However, the inhibitory collagen receptor, leukocyte associated IgG-like receptor-1 (LAIR-1), was increased with each cellular division, reaching 2-3 fold over non-dividing cells in response to IL-7 and IL-15. Such changes were not observed with anti-CD3/CD28 stimulation. Western blot analysis revealed no difference in cyclins, cyclin-dependant kinase (CDK)4, p21, p27, or STAT3/5 phosphorylation in collagen matrix, but did reveal reduced expression of the cell cycle regulator CDK6. These data provides rational for the future study of LAIR-1 in T-cell homeostasis and indicates that collagen adhesion may provide spatial repression from the microenvironment during homeostatic expansion.