Novel inflammatory mechanism that transiently prevents the trafficking of immune cells, lymphocytes, into lymph nodes

26 Oct 2017

Novel inflammatory mechanism that transiently prevents the trafficking of immune cells, lymphocytes, into lymph nodes


By Dr Soumen Basak, Intermediate Fellow

NII, New Delhi

Recent research from our group that employed a combination of biochemical, genetic, immunological and mathematical modeling tools, reveals an inhibitory molecular pathway inside the cell, involving inflammatory proteins, that transiently inhibits the invasion of immune cells at the site of infection.


Lymphocytes are immune cells, which play a critical role in the recognition as well as clearance of microbial pathogens. The recognition of pathogen-derived antigens occurs in the secondary lymphoid organs (SLO) that are strategically located throughout the body. As one can imagine, lymphocytes are required to enter continuously in these SLOs, a process facilitated by homeostatic chemokines, for surveillance. Once these lymphocytes encounter antigens in SLOs, they undergo activation and rapid expansion that culminate into appropriate adaptive immune responses against pathogens.


But do we need the continued influx of lymphocytes in an otherwise inflamed SLO, which is hosting rapid expansion of the already antigen-activated pool of lymphocytes? Our collaborative study that was recently published in the EMBO journal reveals that the proinflammatory protein, TNF, produced during immune activation, temporarily prevents the further influx of lymphocytes into inflamed SLOs of immunized mice. TNF disrupted lymphocyte trafficking by downregulating homeostatic chemokines. As such, the expression of these chemokines requires partial protein breakdown of the NF-kappaB signal transducer protein, p100 into p52 by the noncanonical NF-kappaB pathway. Our work demonstrates that TNF obstructs processing of p100 into p52 by noncanonical signaling for downregulating homeostatic chemokines in inflamed SLOs.


Is this transient inhibition mechanism beneficial or does it exemplify the Achilles’ heel of the immune system? On the one hand, our immune system perhaps evolved this mechanism to ensure that local, available resources are entirely used for supporting the expansion of already activated immune cells in inflamed SLOs. But transient disruption of lymphocyte trafficking in inflamed SLOs may have detrimental consequences as well. It is likely to generate vulnerability in an individual fighting against a primary infection to a subsequent assault by a different pathogen. Further understanding of this immune-modulatory mechanism may provide for therapeutic calibration of physiological immune responses.


A TNFp100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs. Tapas Mukherjee, Budhaditya Chatterjee, Atika Dhar, Sachendra S Bais, Meenakshi Chawla, Payel Roy, Anna George, Vineeta Bal, Satyajit Rath, Soumen Basak. The EMBO Journal. October 2017


Banner image credit:  Peter Lane and Fiona McConnell, Wellcome Images . Normal spleen showing B cells and T cells