Immunology Faculty Member - Shiv Pillai, MD, PhD

Shiv Pillai, MD, PhD

Program Head, Graduate Program in Immunology
Director, MMSc in Immunology Program

Ragon Institute of MGH, MIT and Harvard
400 Tech Square
Cambridge, MA 02139
Tel: 857-268-7005
Email: pillai@helix.mgh.harvard.edu
Lab Members: 3 Instructors, 4 Postdoctoral Fellows, 2 Graduate Students

We ask questions about the biology of the immune system and susceptibility to disease. Some of these questions are 1) can we manipulate the immune system to treat autoimmunity and cancer and to increase immunological memory? 2) can we understand how genetics and the environment affect lymphoid clones to drive common diseases? and 3) can this latter information be used to better understand and develop new therapies for inflammatory human diseases such as COVID-19, systemic sclerosis and IgG4-related disease? We have discovered an underlying basis for why natural infection will not lead to herd immunity in COVID-19, emphasizing the need for vaccination. Our earlier discovery of the role of an enzyme called Btk in the activation of B cells has contributed to the generation of Btk inhibitors that are effective in B cell malignancies and in trials of autoimmunity. One of the pathways we are currently studying suggests new approaches for the treatment of autoimmune disorders.

Pathogenesis of Inflammatory diseases (NIAID Autoimmune Center of Excellence at MGH)
In studies on COVID-19 we have described the underlying reason for the defect in humoral immunity by interrogating immune activation processes in lymph nodes, spleen and the blood. We have shown that a block in the final stage of T follicular helper cell differentiation leads to the collapse of germinal centers and accounts for the lack of durable immunity. A detailed understanding of adaptive immune changes in the lung in COVID-19 has also been obtained. In systemic sclerosis and IgG4-related disease we have shown that apoptosis of specific cell types in each disease, induced by cytotoxic T cells, is a prelude to fibrosis.

Studies on murine and human B and T cell biology
We are using a number of single cell transcriptomic, epigenetic and genetic approaches to examine the heterogeneity, development and biology of selected murine and human B and T cells, in particular cytotoxic CD4+ T cells, T follicular helper cells, Transitional H cells, double negative disease related B cell subsets as well as the molecular bases of the processes of T-B collaboration and germinal center formation and how these processes may be abrogated in human disease.

DNA methylation, B cell self-renewal and chronic lymphocytic leukemia
We have long been interested in cell fate decisions in B cell development and in the development of self-renewing B cell subsets. The roles of DNMT3a in B-1a B cell self-renewal and of specific methylation events in chronic lymphocytic leukemia are being investigated. The contributions of DNA methylation and demethylation to the biology of CD4+ CTL and TFH cells are also being investigated.

Studies on Human CTLA4 and NFkB1 mutations and early B cell development
The underlying mechanism for the human B cell developmental defect in individuals with CTLA4 and NFkB1 mutations has been studied helping us to better understand how regulatory T cells can influence early B cell development and humoral autoimmunity.

Last Update: 8/17/2020

Publications

Kaneko N, Kuo HH, Boucau J, Farmer JR, Allard-Chamard H,Mahajan VS, Piechocka-Trocha A, Lefteri K, Osborn M, Bals J, Bartsch YC, Bonheur N, Caradonna TM, Chevalier J, Chowdhury F, Diefenbach TJ, Einkauf K, Fallon J, Feldman J, Finn KK, Garcia-Broncano P, Hartana CA, Hauser BM, Jiang C, Kaplonek P, Karpell K, Koscher EC, Lian X, Liu H, Liu J, Ly NL, Michell AR, Rassadkina Y, Seiger K, Sessa L, Shin S, Singh N, Sun W, Sun X, Ticheli HJ, Waring MT, Zhu AL, Li JZ, Lingwood D, Schmidt AG, Lichterfeld M, Walker BD, Yu X, Padera RF, Pillai S and Group MCPRSW (2020) Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell, in press. PMID: 32742244

Maehara T*, Kaneko N*, Perugino CA*, Mattoo H, Kers J, Allard-Chamard H, Mahajan VS, Liu H, Murphy SJH, Ghebremichael M, Fox D, Payne AS, Lafyatis R, Stone JH, Khanna D, Pillai S (2020). CD4+ cytotoxic T lymphocytes and apoptosis of HLA-DR expressing endothelial cells in systemic sclerosis J Clin Invest. 130, 2451-2464.

Perugino CA, Kaneko N, Maehara T, Mattoo H, Kers J, Allard-Chamard H, Mahajan VS, Liu H, Della-Torre E, Murphy SJH, Ghebremichael M, Wallace ZS, Bolster MB, Harvey LM, Mylvaganam G, Tuncay Y, Liang L, Montesis SB, Zhang X, Tinju A, Mochizuki K, Munemura R, Sakamoto M, Moriyama M, Nakamura S, Yosef N, Stone JH, Pillai S (2020) CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease. J Allergy Clin Immunol. S0091-6749(20)30741-7.

Farmer J, Allard-Chamard H, Sun N, Bertocchi A, Mahajan VS,Aicher T, Arnold J, Benson MD, Morningstar J, Barmettler S, Yuen J, Murphy SJH, Walter JR, Ghebremichael M, Shalek AK, Gerzsten R, Pillai S (2019) Decreased mTORC1 signaling and induction of metabolic quiescence define the transitional to follicular B cell switch. Science Signaling 2019 12(604). pii: eaaw5573. doi: 10.1126/scisignal.aaw5573

Della-Torre E, Rigamonti E, Perugino C, Sain SB, Sun N, Maehara T, Kaneko N, Rovati L, Lanzillota M, Mahajan V, Mattoo H, Molineris I, Deshpande V, Stone JH, Falconi F, Manfredi AA and Pillai S (2019). B lymphocytes directly contribute to fibrosis in IgG4-related disease. Journal of Allergy and Clinical Immunology. 145, 968-981

Netravali IA, Caraiappa A, Yates K, Haining WN, Bertocchi SA, Allard-Chamard H, Rosenberg I, Pillai S (2019). 9-O-acetyl sialic acid levels identify committed progenitors of plasmacytoid dendritic cells Glycobiology 29:861-875.