Regulation of T Lymphocyte Growth By Macropinocytosis

Abstract

Macropinocytosis is a non-selective form of clathrin-independent endocytosis that has been conserved by evolution from unicellular amoeboids to mammals. The function of macropinocytosis in various cell types, however, is distinct. In amoebae, macropinocytosis facilitates feeding. In mammalian cells it has been shown to aid in, among other things, regulation of receptor density, directed migration, and antigen presentation. Macropinocytosis is implicated in a range of human diseases, including atherosclerosis and transmissable spongiform encephalopathies, as well as being a commonly exploited route of viral infection.

We have discovered that primary mouse and human T lymphocytes (T cells) engage in constitutive macropinocytosis that is enhanced significantly upon TCR ligation and co-stimulation. Unlike macropinocytosis in many other cell types, T cell macropinocytosis is also Ras-independent. We have shown that macropinocytosis is essential for G1 phase growth in activated T cells even under nutrient-replete conditions. Mechanistically, macropinocytosis enables rapid T cell growth, at least in part, by delivering free amino acids obtained from the extracellular space to the lysosomal compartment. There they promote the activation of the mechanistic target of rapamycin complex 1 (mTORC1) by an inside-out signaling mechanism to drive G1 phase blastogenesis and subsequent clonal expansion. Supplementation of minimal cell culture media with the amino acids leucine, glutamine, arginine and serine is sufficient to sustain mTORC1 activation in this period, with leucine and arginine being most important among these.

This work constitutes the first demonstration of a role for macropinocytosis in the regulation of non-cancerous mammalian cell growth. These results suggest that macropinocytosis-mediated activation of mTORC1 may be a feature of other highly proliferative cells. Modulation of T cell macropinocytosis may be therapeutic in the setting of diseases of public health interest.