Tracy McGaha, PhD

Cellular communication in homeostatic tolerance
Cells die by the billions through the process of apoptosis on a daily basis. This creates what could be a significant problem given that apoptosis results in the exposure of potentially harmful auto-antigens. However, potent immune suppressive mechanisms driven by apoptotic cells prevent generation of pathologic autoimmunity. While much attention has been devoted to understanding the soluble effectors involved in this process, there is substantially less known regarding the complex cellular communication involved in apoptotic cell-driven suppression in vivo. My laboratory uses an in vivo model of apoptotic cell challenge testing potential mechanism involved in the innate response elicited by tissue-resident macrophages and dendritic cells. In particular we are interested in apoptotic cell-driven chemotaxis and functional interactions between tissue resident macrophages, tolerogenic CD103+ dendritic cells and regulatory T cell populations.

Cellular stress in myeloid function
We are also interested in the mechanisms by which metabolic stress signals and innate signaling influence immune responses to apoptotic cell death and downstream suppression. We have found that the integrated stress response kinase GCN2 and the DNA-sensing pathways play a key role in tolerogenic maturation of macrophages and dendritic cells after apoptotic cell phagocytosis; however, the cellular and molecular mechanisms through which GCN2 induces this effect are not known. Thus, we are examining the mechanistic role for GCN2 in homeostatic maintenance of tolerance to apoptotic self and contribution of these mechanisms to pathology associated with autoimmunity. Moreover, we have strong evidence that GCN2-driven myeloid function is a significant contributing factor to immune suppression associated with solid tumours. In a related project, we are testing molecular mechanisms through which GCN2 influences tumour-driven myelopoiesis and immune suppression in the tumour and draining lymph nodes. We are particularly interested in cross talk between GCN2 and mammalian target of rapamycin (mTOR); evidence suggests that these micro-environmental nutrient sensor pathways are interdependent.

Related Links

J Immunol. 2019 Nov 15;203(10):2588-2601
Drohomyrecky PC, Doroshenko ER, Akkermann R, Moshkova M, Yi TJ, Zhao FL, Ahn JJ, McGaha TL, Pahan K, Dunn SE
Front Oncol. 2019;9:415
Gadalla R, Noamani B, MacLeod BL, Dickson RJ, Guo M, Xu W, Lukhele S, Elsaesser HJ, Razak ARA, Hirano N, McGaha TL, Wang B, Butler M, Guidos CJ, Ohashi PS, Siu LL, Brooks DG
J Immunother Cancer. 2019 Mar 13;7(1):72
Clouthier DL, Lien SC, Yang SYC, Nguyen LT, Manem VSK, Gray D, Ryczko M, Razak ARA, Lewin J, Lheureux S, Colombo I, Bedard PL, Cescon D, Spreafico A, Butler MO, Hansen AR, Jang RW, Ghai S, Weinreb I, Sotov V, Gadalla R, Noamani B, Guo M, Elston S,...
Proc Natl Acad Sci U S A. 2019 Feb 15;:
Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, Chu MF, Hodgson K, Berger T, Wakeham A, Palomero L, Garcia-Valero M, Pujana MA, Mak TW, McGaha TL, Cappello P, Gorrini C
Trends Immunol. 2018 Nov 05;:
Shinde R, McGaha TL
Immunity. 2018 Oct 01;:
Snell LM, MacLeod BL, Law JC, Osokine I, Elsaesser HJ, Hezaveh K, Dickson RJ, Gavin MA, Guidos CJ, McGaha TL, Brooks DG
Nat Immunol. 2018 May 14;:
Shinde R, Hezaveh K, Halaby MJ, Kloetgen A, Chakravarthy A, da Silva Medina T, Deol R, Manion KP, Baglaenko Y, Eldh M, Lamorte S, Wallace D, Chodisetti SB, Ravishankar B, Liu H, Chaudhary K, Munn DH, Tsirigos A, Madaio M, Gabrielsson S, Touma Z, Wither...
Bioorg Med Chem Lett. 2017 Oct 15;27(20):4597-4600
McQueen A, Blake LD, Azhari A, Kemp MT, McGaha TW, Namelikonda N, Larsen RW, Manetsch R, Kyle DE
Trends Immunol. 2017 Aug;38(8):542-557
Snell LM, McGaha TL, Brooks DG


Associate Professor, Department of Immunology, University of Toronto