Naresha Saligrama, PhD

Assistant Professor
Neurology

Immunology Program
Neurosciences Program
Biomedical Informatics and Data Science Program

  • 7612 BJCIH

  • nareshas@wustl.edu

  • http://saligramalab.org

  • @SaligramaLab

  • Neuroimmunology, Autoimmunity, T cell receptors, Antigens

  • Adaptive immune responses in neuroinflammatory, neurodegenerative, and neuropsychiatric diseases

Research Abstract:

T CELL RECEPTOR REPERTOIRE IN AUTOIMMUNITY
Over the years, several genome wide associations studies (GWAS) have been done on many autoimmune diseases. These GWAS suggests susceptibility to Multiple sclerosis (MS), and other autoimmune diseases are highly associated with specific major histocompatibility complex (MHC) class II alleles with only weak or negligible class I MHC associations. Because of strong Class II association, a majority of the studies in MS and Experimental autoimmune encephalomyelitis (EAE, an induced mouse model for MS) have been focused on CD4 T cells. Undoubtedly, GWAS helped to pinpoint the genetic factors underlying the pathophysiology of MS, it failed at a systems level to provide a mechanistic understanding of the cellular adaptive immunity. More recently, we have shown that simultaneous mobilization of oligoclonal CD4, CD8, and γδ T cells expressing an activated phenotype occurs not only in EAE, but also in newly diagnosed MS patients. This suggests that all three T cell types are activated and recruited concurrently as part of a concerted and specific immune response. Moreover, in EAE we show that the fraction of clonally expanded CD8 T cells suppress autoreactive CD4 T cells (Saligrama et al., 2019).

T CELL SPECIFICITY AND FUNCTION IN AUTOIMMUNITY
A long standing question in autoimmunity and MS is what causes/triggers the disease. αβ T cells recognize peptide antigens presented on MHC/HLA molecules. Since the cloning of TCR in mouse and human, we have learned quite a bit about the rearrangement of TCRs, signaling, and how they recognize peptide antigens. Recent development of paired TCR sequencing at a single cell level, has enabled us to understand the TCR repertoire in various disease settings in an unprecedented level. However, we still lack tools to leverage TCR sequence information to determine their specificity. To better bridge TCR sequence information to its specificity, we and others have developed computational and high-throughput methods. In contrast to traditional methods, our approach helps identify the T cells that are most active in a given response (autoimmunity) by single cell paired TCR sequencing and ligand identification either with a yeast display library, or candidate antigens and reporter cells transfected with the relevant TCR pairs.

SYSTEMS ANALYSIS OF ADAPTIVE IMMUNITY IN NEUROLOGICAL DISORDERS
MS is a quintessential autoimmune neuroinflammatory disease. It is becoming more and more evident that inflammation and adaptive immune cells play a role in aging and other neurodegenerative, and neuropsychiatric diseases. The recent identification of α-syn-specific T cells in Parkinson’s Disease (PD) patients with α-syn pathology raises an interesting possibility of autoimmune component in PD. In a collaborative effort, we have shown an interaction of T cells and neural stem cells in old brain, highlighting the neuroimmune interactions in aging.
Specifically in humans, we are interested in understanding 1) At a systems level the changes in the immune system in aging and 2) The contribution of chronic inflammatory immune response on central nervous system neurodegeneration with a focus to understand the neuroimmune interactions.

Selected Publications:

Saligrama N, Zhao F*, Sikora MJ*, Serratelli WS, Fernandes RA, Louis MD, Winnie Y, Xuhuai Ji, Idoyaga J, Mahajan VB, Steinmetz LM, Chien YH, Hauser SL, Oksenberg JR, Garcia KC, and Davis MM. Opposing T cell responses in Experimental Autoimmune Encephalomyelitis. *contributed equally
Nature. 572, 481-487 (2019). PMID:31391585

Dulken BW*, Buckley MT*, Negredo PN*, Saligrama N, Cayrol R, Leeman DS, George B, Boutet SC, Hebestreit K, Pluvinage JV, Wyss-Coray T, Weissman IL, Vogel H, Davis MM, and BrunetA. (2019). Single cell analysis of neurogenic niches during aging reveals age-dependent cell composition changes and interaction between T cells and neural stem cells.*contributed equally
Nature. 571, 205-210 (2019). PMID:31270459

Satpathy AT*, Saligrama N*, Buenrostro JD*, Wei Y, Wu B, Rubin AJ, Granja JM, Li R, Lareau CA, Li R, Qi Y, Parker KR, Mumbach MR, Serratelli WS, Gennert DG, Schep AN, Corces MR, Khodadoust MS, Kim YH, Khavari PA, Greenleaf WJ, Davis MM, and Chang HY. Transcript-indexed ATAC-seq for precision immune profiling. **Co-first authors, *contributed equally
Nature Medicine.24, 580-590.2018. PMID:29686426

Mamedov MR, Scholzen A, Nair RV, Cumnock K, Kenkel JA, Oliveira JHM, Trujillo DL, Saligrama N, Zhang Y, Rubelt F, Schneider DS, Chien YH, Sauerwein RW, and Davis MM. A macrophage colony-stimulating factor producing γδ T cell subset prevents malarial parasitemic recurrence.
Immunity. 48 (2): 350-363. 2018. PMID:29426701

Last Updated: 9/30/2021 12:59:20 PM

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