University of Poona, India
University of Bombay, India
Haffkine Institute, Mumbai
London University, UK.
Analysing roles of T lymphocytes in pathophysiological conditions.
PhD students : Sanket Rane, Arundhoti Das, Parna Kanodia and Neelam Oswal.
Project associate: Saptak Banerjee
Collaborators: Anna George, Satyajit Rath from NII; B Ravindran from ILS, Bhubaneswar; Shinjini Bhatnagar, U. C. Mouli Natchu, Guruprasad Medigeshi, Nitya Wadhwa, Shailaja Sopory and Sudhanshu Vrati from THSTI, Gurgaon; Arvind Bagga, Pankaj Hari and Aditi Sinha from AIIMS, New Delhi; and Jeannine Durdik from the University of Arkansas, USA.
Summary of Research
The lab has been looking at the pathways regulating the functional fate of T lymphocytes in immune responses and their phenotypic characterisation in steady state in extensive collaborative efforts within and outside NII.
CD4 T cells make various cell-fate decisions depending upon the environment they live in and the signals they receive through their cell surface receptors. We hypothesised that despite unimodal distribution of CD4 co-receptor on naïve CD4 T cells they are not homogenous in their function. By testing naïve CD4 population from mice and humans expressing highest and lowest (~10%) levels of CD4 in a variety of functional assays we find that indeed naïve CD4 cells with high CD4 levels respond much better to activation and survive more easily post-activation. With longer in vivo survival naïve CD4 cells lose CD4 levels and become less responsive. This loss of response is dependent on tonic signals received in vivo, and is regulated by erk-DUSP6-miRNA181a levels. Naïve cells from aged mice show a pattern similar to that observed in naïve CD4 cells from young mice with lower CD4 levels.
Another aspect of cell fate decision under study is evaluation of ex vivo CD4 memory T cells for their Th1/Th2 differentiation pattern and compare it with the intrinsic tendency of naive CD4 T cells to differentiate into Th1 or Th2 cells, in the absence of environmentally driven differentiation programme. We observe that ex vivo memory CD4 cells co-express t-bet and gata-3 in large proportion of cells, however, these cells produce only Th1 or Th2 effector cytokines, not both. In vitro generated CD4 memory cells also behave similarly. Human CD4 cells behave also show the same pattern. We are attempting to understand the mechanisms for these observations and also trying to correlate with human diseases such as Nephrotic Syndrome.
Nephrotic syndrome is a common disease in paediatric age-group and a signficant proportion of cases become resistant to corticoid treatment. In addition to work on human patients, we are using mouse model of LPS-mediated albuminuria to dissect pathways critical for the induction of albuminuria and associated pathology.
Humans infected with Japanese encephalitis virus can face varying levels of morbidity and the disease can also be fatal. Using mouse models we are trying to identify components of the adaptive immune system which are critically involved in the development of pathology.
- Rathore DK, Nair D, Raza S, Saini S, Singh R, Kumar A, Tripathi R, Ramji S, Batra A, Aggarwal KC, Chellani HK, Arya S, Bhatla N, Paul VK, Aggarwal R, Agarwal N, Mehta U, Sopory S, Natchu UCM, Bhatnagar S, Bal V, Rath S and Wadhwa N (2015). Underweight full-term Indian neonates show differences in umbilical cord blood leukocyte phenotype: a cross-sectional study. PLoS One 10, e0123589.
- Rane S, Das R, Ranganathan V, Prabhu S, Das A, Mattoo H, Durdik JM*, George A*, Rath S*, Bal V* (2014) Peripheral residence of naïve CD4 T cells induces MHC class II-dependent alterations in phenotype and function. BMC Biology 12, 106.
- Saini S, Shenoy G, Rath S*, Bal V*, George A* (2014) Inducible nitric oxide synthase is a major intermediate in signaling pathways for the survival of plasma cells. Nature Immunology 15, 275-282.
- Upadhyay M, Priya GK, Ramesh P, Madhavi MB, Rath S, Bal V, George A and Vaidya T. (2014) Journal of Cellular Physiology CD40 signaling drives B lymphocytes into an intermediate memory-like state, poised between naïve and plasma cells. Published online: Jan 31. doi: 10.1002/jcp.24572.
- Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, Saini H, Kotresh ST, Ali U, Bhatia D, Ohri A, Kumar M, Agarwal I, Gulati S, Anand K, Vijaykumar M, Sinha R, Sethi S, Saloma M, George A, Bal V, Singh G, Dinda AK, Hari P, Rath S, Dragon-Durey M-A, Bagga A. (2014) Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney International 85 1151-1160.
- Banerjee H, Das A, Srivastava S, Mattoo HR, Thyagarajan K, Khalsa JK, Tanwar S, Sharma D, Majumdar SS, George A*, Bal V*, Durdik JM*, Rath S*. (2012) A role for apoptosis-inducing factor (Aif) in T cell development. J Exp Med 209 1641-1653.
- Shenoy GN, Chatterjee P, Kaw S, Mukherjee S, Rathore DK, Bal V*, Rath S*, George A*. (2012) Recruitment of memory B cells to lymph nodes remote from the site of immunization requires an inflammatory stimulus. J Immunol 189 521-528.
- Panda S, Kumar S, Tupperwar N, Vaidya T, George A, Rath S, Bal V, Ravindran B. (2012) Chitohexaose activates macrophages by alternate pathway through TLR4 and blocks endotoxemia. PLoS Pathogens 8 e1002717.
- Chatterjee P, Tiwari RK, Rath S*, Bal V*, George A*. (2012) Modulation of antigen presentation and BCR signaling in B cells of beige mice. J Immunol 188 695-702.
- Khare A, Viswanathan B, Gund R, Jain N, Ravindran B, George A*, Rath S*, Bal V*. (2011) Role of Bruton’s tyrosine kinase in macrophage apoptosis. Apoptosis 16 334-336.
* indicates joint senior authorship.