Rahul Roychoudhuri

The Roychoudhuri group has relocated to the University of Cambridge Department of Pathology where Rahul Roychoudhuri has taken up a University Senior Lectureship as of June 1st 2020. Visit the Roychoudhuri Group webpage for full details of the group's current research.

Immunoregulation: Uncovering the 'brakes' on immune activation CD4+ and CD8+ T cells have a powerful ability to drive immune activation and promote clearance of infections and cancer. However, their function can also promote deleterious autoimmune and allergic inflammation. The immune system therefore employs a variety of suppressive mechanisms, collectively referred to as immunoregulatory mechanisms, to restrain excessive immune activation.

While immunoregulatory mechanisms play a beneficial role in preventing inflammation, they can also powerfully suppress immune responses during chronic infections and cancer in a process referred to as immunosuppression. Immunoregulatory mechanisms therefore function as 'brakes' on immune activation and are important therapeutic targets.

Our research aims to understand the molecular and cellular mechanisms of tolerance and immunosuppression in physiology, and during infection, inflammation and cancer. We hope that this will enable development of new therapies aimed at manipulating immune function in patients with inflammation and cancer.


Latest Publications

BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression.
Grant FM, Yang J, Nasrallah R, Clarke J, Sadiyah F, Whiteside SK, Imianowski CJ, Kuo P, Vardaka P, Todorov T, Zandhuis N, Patrascan I, Tough DF, Kometani K, Eil R, Kurosaki T, Okkenhaug K, Roychoudhuri R

Regulatory T (Treg) cell populations are composed of functionally quiescent resting Treg (rTreg) cells which differentiate into activated Treg (aTreg) cells upon antigen stimulation. How rTreg cells remain quiescent despite chronic exposure to cognate self- and foreign antigens is unclear. The transcription factor BACH2 is critical for early Treg lineage specification, but its function following lineage commitment is unresolved. Here, we show that BACH2 is repurposed following Treg lineage commitment and promotes the quiescence and long-term maintenance of rTreg cells. Bach2 is highly expressed in rTreg cells but is down-regulated in aTreg cells and during inflammation. In rTreg cells, BACH2 binds to enhancers of genes involved in aTreg differentiation and represses their TCR-driven induction by competing with AP-1 factors for DNA binding. This function promotes rTreg cell quiescence and long-term maintenance and is required for immune homeostasis and durable immunosuppression in cancer. Thus, BACH2 supports a "division of labor" between quiescent rTreg cells and their activated progeny in Treg maintenance and function, respectively.

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The Journal of experimental medicine, 217, 9, 07 Sep 2020

DOI: 10.1084/jem.20190711

PMID: 32515782

A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by T cells.
Nasrallah R, Imianowski CJ, Bossini-Castillo L, Grant FM, Dogan M, Placek L, Kozhaya L, Kuo P, Sadiyah F, Whiteside SK, Mumbach MR, Glinos D, Vardaka P, Whyte CE, Lozano T, Fujita T, Fujii H, Liston A, Andrews S, Cozzani A, Yang J, Mitra S, Lugli E, Chang HY, Unutmaz D, Trynka G, Roychoudhuri R

Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.5 contains a distal enhancer that is functional in CD4 regulatory T (T) cells and required for T-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-κB to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3 T cells, which are unable to control colitis in a cell-transfer model of the disease. In human T cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.

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Nature, 1, 1, 13 May 2020

DOI: 10.1038/s41586-020-2296-7

PMID: 32499651

IRF4 instructs effector Treg differentiation and immune suppression in human cancer.
Alvisi G, Brummelman J, Puccio S, Mazza EMC, Paoluzzi Tomada E, Losurdo A, Zanon V, Peano C, Colombo FS, Scarpa A, Alloisio M, Vasanthakumar A, Roychoudhuri R, Kallikourdis M, Pagani M, Lopci E, Novellis P, Blume J, Kallies A, Veronesi G, Lugli E

The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ regulatory T cells (Tregs) in tumors are poorly known. High-dimensional single cell profiling of T cells from chemotherapy-naïve individuals with non-small cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespectively of the tumor type.

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The Journal of clinical investigation, 1, 1, 03 Mar 2020

DOI: 10.1172/JCI130426

PMID: 32125291