UC Berkeley

Abstract

Role of Necroptosis in T Cell Activation

by

Zhanran Zhao

Doctor of Philosophy in Molecular and Cell Biology

University of California, Berkeley

Professor Astar Winoto, Chair

Necroptosis is a programmed cell death pathway characterized by a necrosis-like

morphology and mediated in part by the kinase activity of receptor-interacting protein kinase 3

(RIPK3) and, in most cases, its partner RIP1 as well. Necroptosis is a hidden cell death pathway,

as it was initially only described in cells deficient in FADD or caspase-8. Necroptosis has been

shown to play important roles in injury, disease models, and, more recently, in certain viral

infections. However, its role in a normal physiological setting is still not completely clear. Using

Nec-1, an inhibitor of RIP1 kinase activity, we have previously shown that a proportion of CD8

T cells can be rescued from cell death induced by TCR activation in vitro. This observation led

us to characterize the phenotype of T cells from mice deficient in RIP3 to examine the role

necroptosis plays in T cell activation. We found that inhibiting necroptosis can lead to increased

cell number and activity of cytotoxic T lymphocytes (CTLs). Furthermore, Rip3-/- mice showed

improved tumor responses compared to littermate controls, with decreased expression of

inhibitory markers on CTLs and reduced suppressive Treg populations in the tumor infiltrating

lymphocytes. Using adoptive transfer, we showed that this effect is primarily driven by Rip3-/- T

cells and that these T cells exhibit elevated activation activities and improved anti-tumor

function. Necroptosis thus helps to regulate T cell activation to maintain the delicate balance of

immune homeostasis.