Linda Bradley's Research Focus
The research program in the Bradley Lab is focused on understanding the regulation of T lymphocytes in virus infections where the immune response results in viral clearance and the development of immunologic memory, and in chronic virus infections where the ongoing immune response leads to viral persistence and immune dysregulation. We are guided by these studies to interrogate cellular mechanisms that can be modulated to promote better responses not only to virus infections, but also to relieve immune inhibition in the setting of cancer where T cells progressively lose function. Understanding adhesion mechanisms underlie the ability of T cells to become localized in tissues to eradicate infections and tumors is a key underpinning of our work.
Our current focus is on two molecules that can function on T cells to initiate the processes that lead to their migration from the blood into tissue, CD44 and PSGL-1 (P-selectin glycoprotein-1). We have found that both of these receptors have key regulatory functions that are independent of their roles in migration. These proteins regulate the magnitude of T cell responses, as well as the survival and memory formation by T cells by different mechanisms, affecting processes in the T cell and stromal cell compartments.
Our ongoing studies of these immune checkpoint regulators using in vivo models indicate that they are promising therapeutic targets to enhance T cell responses to infections and cancer as well as to inhibit T cell responses in autoimmunity. We are therefore pursuing translational studies with the UCSD Moores Cancer center to analyze their regulation in human T cells in an effort to enhance patient responses to their tumors using in vivo modeling. In addition working to develop biologics for treatment of patients with autoimmunity and cancer.
Linda Bradley's Bio
Dr. Bradley received her doctorate from the University of California Berkeley, in 1981 in studies of CD4 T cell subsets that regulate humoral immune responses. Her work on the regulation of CD4 T cells continued during her postdoctoral training at The Oregon Primate Research Center and at the University of California, San Diego where she was appointed Assistant Research Professor in 1991. It was at this time she developed NIH sponsored her research program on CD4 T cells and discovered the key associations between migration and function. She joined The Scripps Research institute as an Assistant Professor in 1996 where she expanded her work on CD4 T cells into the arena of autoimmunity and discovered the essential role of the cytokine, interleukin-7, in the regulation of CD4 cell homeostasis.
She joined the Sidney Kimmel Cancer Center in 2001 as an Associate Professor, and was promoted to Professor in 2005. She joined Sanford Burnham Prebys as a Professor in the Infectious and Inflammatory Diseases Center in 2009. Dr. Bradley is recognized as a key contributor in the field of CD4 T cell biology, is an invited speaker at many national and international meetings, and serves on several study sections for the NIH as well as the Welcome Trust, Medical Research Council, and the JDRF.
Striking a Balance-Cellular and Molecular Drivers of Memory T Cell Development and Responses to Chronic Stimulation.
Hope JL, Stairiker CJ, Bae EA, Otero DC, Bradley LM
Front Immunol 2019 ;10:1595
Tinoco R, Otero DC, Takahashi AA, Bradley LM
Trends Immunol 2017 May ;38(5):323-335
Tinoco R, Carrette F, Barraza ML, Otero DC, Magaña J, Bosenberg MW, Swain SL, Bradley LM
Immunity 2016 May 17 ;44(5):1190-203
PSGL-1 attenuates early TCR signaling to suppress CD8(+) T cell progenitor differentiation and elicit terminal CD8(+) T cell exhaustion.
Hope JL, Otero DC, Bae EA, Stairiker CJ, Palete AB, Faso HA, Lin M, Henriquez ML, Roy S, Seo H, Lei X, Wang ES, Chow S, Tinoco R, Daniels GA, Yip K, Campos AR, Yin J, Adams PD, Rao A, Bradley LM
Cell Rep 2023 Apr 26 ;42(5):112436
Ubiquitin ligases Siah1a/2 control alveolar macrophage functions to limit carcinogen-induced lung adenocarcinoma.
Scortegagna M, Du Y, Bradley LM, Wang K, Molinolo A, Ruppin E, Murad R, Ronai ZA
Cancer Res 2023 Apr 19 ;
Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries.
Reches G, Blondheim Shraga NR, Carrette F, Malka A, Saleev N, Gubbay Y, Ertracht O, Haviv I, Bradley LM, Levine F, Piran R
Inflamm Regen 2022 Nov 29 ;42(1):52
Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities.
Lu Z, Bae EA, Verginadis II, Zhang H, Cho C, McBrearty N, George SS, Diehl JA, Koumenis C, Bradley LM, Fuchs SY
Cancer Immunol Immunother 2023 Apr ;72(4):815-826
MicroRNA-139 Expression Is Dispensable for the Generation of Influenza-Specific CD8(+) T Cell Responses.
Hope JL, Zhao M, Stairiker CJ, Kiernan CH, Carey AJ, Mueller YM, van Meurs M, Brouwers-Haspels I, Otero DC, Bae EA, Faso HA, Maas A, de Looper H, Fortina PM, Rigoutsos I, Bradley LM, Erkeland SJ, Katsikis PD
J Immunol 2022 Feb 1 ;208(3):603-617
Garancher A, Suzuki H, Haricharan S, Chau LQ, Masihi MB, Rusert JM, Norris PS, Carrette F, Romero MM, Morrissy SA, Skowron P, Cavalli FMG, Farooq H, Ramaswamy V, Jones SJM, Moore RA, Mungall AJ, Ma Y, Thiessen N, Li Y, Morcavallo A, Qi L, Kogiso M, Du Y, Baxter P, Henderson JJ, Crawford JR, Levy ML, Olson JM, Cho YJ, Deshpande AJ, Li XN, Chesler L, Marra MA, Wajant H, Becher OJ, Bradley LM, Ware CF, Taylor MD, Wechsler-Reya RJ
Nat Neurosci 2022 Jan ;25(1):127