Linda Bradley, Ph.D.

Linda Bradley's Research Focus

Type 1 Diabetes, Skin Cancer and Melanoma
Immune System and Inflammation

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 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.


IPP Accessory

Publications

CD44 regulates survival and memory development in Th1 cells.

Baaten BJ, Li CR, Deiro MF, Lin MM, Linton PJ, Bradley LM

Immunity 2010 Jan 29 ;32(1):104-15

Polyclonal adaptive regulatory CD4 cells that can reverse type I diabetes become oligoclonal long-term protective memory cells.

Godebu E, Summers-Torres D, Lin MM, Baaten BJ, Bradley LM

J Immunol 2008 Aug 1 ;181(3):1798-805

Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo.

Weber SE, Harbertson J, Godebu E, Mros GA, Padrick RC, Carson BD, Ziegler SF, Bradley LM

J Immunol 2006 Apr 15 ;176(8):4730-9

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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

Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5<sup>-/-</sup> mice.

Li Y, Tinoco R, Elmén L, Segota I, Xian Y, Fujita Y, Sahu A, Zarecki R, Marie K, Feng Y, Khateb A, Frederick DT, Ashkenazi SK, Kim H, Perez EG, Day CP, Segura Muñoz RS, Schmaltz R, Yooseph S, Tam MA, Zhang T, Avitan-Hersh E, Tzur L, Roizman S, Boyango I, Bar-Sela G, Orian A, Kaufman RJ, Bosenberg M, Goding CR, Baaten B, Levesque MP, Dummer R, Brown K, Merlino G, Ruppin E, Flaherty K, Ramer-Tait A, Long T, Peterson SN, Bradley LM, Ronai ZA

Nat Commun 2019 Apr 2 ;10(1):1492

Regulation of S100A8 Stability by RNF5 in Intestinal Epithelial Cells Determines Intestinal Inflammation and Severity of Colitis.

Fujita Y, Khateb A, Li Y, Tinoco R, Zhang T, Bar-Yoseph H, Tam MA, Chowers Y, Sabo E, Gerassy-Vainberg S, Starosvetsky E, James B, Brown K, Shen-Orr SS, Bradley LM, Tessier PA, Ronai ZA

Cell Rep 2018 Sep 18 ;24(12):3296-3311.e6

Nuclear pore complex-mediated modulation of TCR signaling is required for naïve CD4<sup>+</sup> T cell homeostasis.

Borlido J, Sakuma S, Raices M, Carrette F, Tinoco R, Bradley LM, D'Angelo MA

Nat Immunol 2018 Jun ;19(6):594-605

Targeting the PSGL-1 pathway for immune modulation.

Tinoco R, Bradley LM

Immunotherapy 2017 Sep ;9(10):785-788

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