Life Sciences Research for Lifelong Health

Michelle Linterman

Research Summary

When higher organisms are infected by pathogens the immune system responds with the coordinated activation of many different cell types, each with their own specific role to bring about pathogen clearance, and subsequently generate immunological memory. Within the adaptive immune system helper CD4+ T cells and B cells specific for the infectious organism are recruited to become activated effector cells and a proportion of these cells will go on to become memory cells that are able to respond quickly to future infections.

Germinal centres are sites within tissues such as the tonsils, spleen and lymph nodes where B cells proliferate and differentiate during a normal immune response to an infection. Because of the central role of the germinal centre in generating immunological memory, a potent germinal centre response is critical for a successful response to vaccination. With advancing age, the size of the germinal centre response and the efficacy of vaccination diminish, and T cells are one of the primary contributors to this decline.

Our research is focused on understanding the cellular and molecular changes that occur in T cells with age that contribute to the age-dependent decline in the germinal centre response.

Latest Publications

Regulation of the Germinal Center Response.
Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L

The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3 T follicular regulatory (Tfr) cells are key mediators of GC regulation. However, regulation of GC responses is not a simple outcome of Tfh/Tfr balance, but also involves the contribution of other cell types to modulate the GC microenvironment and to avoid autoimmunity. Thus, the regulation of the GC is complex, and occurs at multiple levels. In this review we outline recent developments in the biology of cell subsets involved in the regulation of GC reactions, in both secondary lymphoid tissues, and Peyer's patches (PPs). We discuss the mechanisms which enable the generation of potent protective humoral immunity whilst GC-derived autoimmunity is avoided.

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Frontiers in immunology, 9, 1664-3224, 2469, 2018

PMID: 30410492

Mice Deficient in Nucleoporin Nup210 Develop Peripheral T Cell Alterations.
van Nieuwenhuijze A, Burton O, Lemaitre P, Denton AE, Cascalho A, Goodchild RE, Malengier-Devlies B, Cauwe B, Linterman MA, Humblet-Baron S, Liston A

The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.

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Frontiers in immunology, 9, 1664-3224, 2234, 2018

PMID: 30323813

Genetic regulation of antibody responsiveness to immunization in substrains of BALB/c mice.
Poyntz HC, Jones A, Jauregui R, Young W, Gestin A, Mooney A, Lamiable O, Altermann E, Schmidt A, Gasser O, Weyrich L, Jolly CJ, Linterman MA, Le Gros G, Hawkins ED, Forbes-Blom E

Antibody-mediated immunity is highly protective against disease. The majority of current vaccines confer protection through humoral immunity, but there is high variability in responsiveness across populations. Identifying immune mechanisms that mediate low antibody responsiveness may provide potential strategies to boost vaccine efficacy. Here, we report diverse antibody responsiveness to unadjuvanted as well as adjuvanted immunization in substrains of BALB/c mice, resulting in high and low antibody response phenotypes. Furthermore, these antibody phenotypes were not affected by changes in environmental factors such as the gut microbiota composition. Antigen-specific B cells following immunization had a marked difference in capability to class-switch, resulting in perturbed IgG isotype antibody production. In vitro, a B cell intrinsic defect in the regulation of class-switch recombination was identified in mice with low IgG antibody production. Whole genome sequencing identified polymorphisms associated with the magnitude of antibody produced, and we propose candidate genes that may regulate isotype class-switching capability. This study highlights that mice sourced from different vendors can have significantly altered humoral immune response profiles, and provides a resource to interrogate genetic regulators of antibody responsiveness. Together these results further our understanding of immune heterogeneity and suggest additional research on the genetic influences of adjuvanted vaccine strategies is warranted for enhancing vaccine efficacy. This article is protected by copyright. All rights reserved.

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Immunology and cell biology, , 1440-1711, , 2018

PMID: 30152893

Group Members

Latest Publications

Regulation of the Germinal Center Response.

Stebegg M, Kumar SD, Silva-Cayetano A

Frontiers in immunology
9 1664-3224:2469 (2018)

PMID: 30410492

Mice Deficient in Nucleoporin Nup210 Develop Peripheral T Cell Alterations.

van Nieuwenhuijze A, Burton O, Lemaitre P

Frontiers in immunology
9 1664-3224:2234 (2018)

PMID: 30323813

Genetic regulation of antibody responsiveness to immunization in substrains of BALB/c mice.

Poyntz HC, Jones A, Jauregui R

Immunology and cell biology
1440-1711: (2018)

PMID: 30152893

The Calcineurin Inhibitor Tacrolimus Specifically Suppresses Human T Follicular Helper Cells.

Wallin EF, Hill DL, Linterman MA

Frontiers in immunology
9 1664-3224:1184 (2018)

PMID: 29904381

TFR cells trump autoimmune antibody responses to limit sedition.

Linterman MA, Toellner KM

Nature immunology
18 1529-2916:1185-1186 (2017)

PMID: 29044242

Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function.

Fonseca VR, Agua-Doce A, Maceiras AR

Science immunology
2 2470-9468: (2017)

PMID: 28802258

Signals that drive T follicular helper cell formation.

Webb LMC, Linterman MA

Immunology
1365-2567: (2017)

PMID: 28628194

Identifying Follicular Regulatory T Cells by Confocal Microscopy.

Vanderleyden I, Linterman MA

Methods in molecular biology (Clifton, N.J.)
1623 1940-6029:87-93 (2017)

PMID: 28589349

No Functional Role for microRNA-342 in a Mouse Model of Pancreatic Acinar Carcinoma.

Dooley J, Lagou V, Pasciuto E

Frontiers in oncology
7 :101 (2017)

PMID: 28573106

BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

Afzali B, Grönholm J, Vandrovcova J

Nature immunology
1529-2916: (2017)

PMID: 28530713

Stromal networking: cellular connections in the germinal centre.

Denton AE, Linterman MA

Current opinion in immunology
45 1879-0372:103-111 (2017)

PMID: 28319729