Academic career
Raulet joined the MIT Department of Biology as an Assistant Professor in 1983 and was promoted to Associate Professor in 1987, receiving tenure in 1990. In 1991, he joined the University of California, Berkeley, where he became Professor in 1993. [7] [3] He served as Head of the Division of Immunology from 1997 to 2003 and later as Co-Chair of the Department of Molecular and Cell Biology from 2012 to 2016. [8]
From 2015 to 2025, he held the Esther and Wendy Schekman Chair in Basic Cancer Biology [9] , and in 2025 he was appointed Professor of the Graduate School and Chair Emeritus. He has directed Berkeley's Immunotherapeutics and Vaccine Research Initiative (IVRI) since 2015. [8]
Research
Raulet's research centers on the innate and adaptive immune response to cancer and viral infection, with particular emphasis on natural killer (NK) [10] cells, gamma-delta T cells, and T lymphocytes. [11] He has authored over 229 scientific publications.
Natural killer cell recognition and "missing self"
Raulet provided some of the earliest and most definitive genetic evidence for the "missing self" hypothesis, demonstrating that NK cells selectively kill otherwise normal cells lacking MHC class I molecules. [12] [13]
His work showed that MHC I-deficient cells are sufficient to trigger NK cell-mediated killing and bone marrow graft rejection. He also showed that NK cells in MHC I deficient mice exhibit impaired functional activity [13] and that a significant percentage of NK cells in normal mice that lack inhibitory receptors for self MHC I similarly exhibit impaired function. [14] He went on to show that NK cells require continuous interaction with self MHC I for full functional activity [15] —a process now known as NK cell education or licensing. His later work demonstrated that NK activity varies continuously depending of the extent of steady state MHC I interactions with inhibitory receptors that NK cells happen to express, a process known as 'tuning'. [16]
Raulet was the first to demonstrate that genes that encode the inhibitory NK cell receptors that recognize MHC I molecules are expressed in a predominantly monoallelic fashion, one of the earliest documented examples of monoallelic autosomal gene expression. [17] [18] Recent work from his lab provides evidence that monoallelic gene expression is characteristic of many or perhaps all genes, though the degree of monoallelic expression is rare for most genes. [19]
NKG2D receptor and tumor surveillance
Raulet was among the first to identify ligands for the NKG2D activating receptor, including RAE-1 and H60 [20] , and demonstrated that expression of these ligands on tumor cells triggers NK-cell-mediated tumor rejection. [21] He further showed that the DNA damage response pathway directly regulate NKG2D ligand expression, linking genomic instability in cancer to immune surveillance. [22] [23] His later work showed that expression of specific NKG2D ligands is also regulated by the unfolded protein stress response [24] , and cellular hyperproliferation. [25]
Using spontaneous mouse cancer models, his laboratory demonstrated that NKG2D-deficient animals exhibit increased susceptibility to tumor development [26] , providing key experimental support for a role of NK cell receptors in cancer immunosurveillance. [27]
STING pathway and cancer immunotherapy
More recent work from the Raulet laboratory developed genetic evidence that activated cGAS, which occurs spontaneously in tumor cells, activates STING in nontumor cells in the tumor microenvironment, leading to cytokine production that mobilizes NK cells against tumors. [28] His group showed that STING agonists can induce NK cell–mediated rejection of tumors resistant to CD8 T cells [29] , and that combination therapy with STING agonists and engineered IL-2 "superkines" produces enhanced antitumor responses by both NK cells and CD8 T cells. [30]
T cell receptor development and MHC restriction
Earlier in his career, Raulet made major contributions to understanding T cell receptor (TCR) gene rearrangement and MHC restriction. He demonstrated that:
- CD8 T cell development requires MHC class I expression [31]
- NKT cell development depends on MHC class I-like molecules [32] [33]
- TCR recognition of MHC is intrinsically encoded in germline gene segments, independent of thymic selection [34]
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