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

Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice.
van Nieuwenhuijze A, Dooley J, Humblet-Baron S, Sreenivasan J, Koenders M, Schlenner SM, Linterman M, Liston A

MicroRNA (miR) are short non-coding RNA sequences of 19-24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the individual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.

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Cellular and molecular life sciences : CMLS, , 1420-9071, , 2017

PMID: 28124096

Shaping Variation in the Human Immune System.
Liston A, Carr EJ, Linterman MA

Immune responses demonstrate a high level of intra-species variation, compensating for the specialization capacity of pathogens. The recent advent of in-depth immune phenotyping projects in large-scale cohorts has allowed a first look into the factors that shape the inter-individual diversity of the human immune system. Genetic approaches have identified genetic diversity as drivers of 20-40% of the variation between the immune systems of individuals. The remaining 60-80% is shaped by intrinsic factors, with age being the predominant factor, as well as by environmental influences, where cohabitation and chronic viral infections were identified as key mediators. We review and integrate the recent in-depth large-scale studies on human immune diversity and its potential impact on health. VIDEO ABSTRACT.

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Trends in immunology, , 1471-4981, , 2016

PMID: 27693120

Can follicular helper T cells be targeted to improve vaccine efficacy?
Linterman MA, Hill DL

The success of most vaccines relies on the generation of antibodies to provide protection against subsequent infection; this in turn depends on a robust germinal centre (GC) response that culminates in the production of long-lived antibody-secreting plasma cells. The size and quality of the GC response are directed by a specialised subset of CD4 (+) T cells: T follicular helper (Tfh) cells. Tfh cells provide growth and differentiation signals to GC B cells and mediate positive selection of high-affinity B cell clones in the GC, thereby determining which B cells exit the GC as plasma cells and memory B cells. Because of their central role in the production of long-lasting humoral immunity, Tfh cells represent an interesting target for rational vaccine design.

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F1000Research, 5, 2046-1402, , 2016

PMID: 26989476

 

Group Members

Latest Publications

Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice.

van Nieuwenhuijze A, Dooley J, Humblet-Baron S

Cellular and molecular life sciences : CMLS
1420-9071: (2017)

PMID: 28124096

Shaping Variation in the Human Immune System.

Liston A, Carr EJ, Linterman MA

Trends in immunology
1471-4981: (2016)

PMID: 27693120

Can follicular helper T cells be targeted to improve vaccine efficacy?

Linterman MA, Hill DL

F1000Research
5 2046-1402: (2016)

PMID: 26989476

Follicular Helper T Cells.

Vinuesa CG, Linterman MA, Yu D

Annual review of immunology
1545-3278: (2016)

PMID: 26907215

The cellular composition of the human immune system is shaped by age and cohabitation.

Carr EJ, Dooley J, Garcia-Perez JE

Nature immunology
1529-2916: (2016)

PMID: 26878114

Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells.

Aloulou M, Carr EJ, Gador M

Nature communications
7 2041-1723:10579 (2016)

PMID: 26818004

Premature thymic involution is independent of structural plasticity of the thymic stroma.

Franckaert D, Schlenner SM, Heirman N

European journal of immunology
1521-4141: (2015)

PMID: 25627671

Regulatory T cells and control of the germinal centre response.

Vanderleyden I, Linterman MA, Smith KG

Arthritis research & therapy
16 1478-6362:471 (2014)

PMID: 25606598

Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3(+) and Foxp3(-) T cells.

Franckaert D, Dooley J, Roos E

Immunology and cell biology
1440-1711: (2014)

PMID: 25533288

Treg cells and CTLA-4: the ball and chain of the germinal center response.

Linterman MA, Denton AE

Immunity
41 1097-4180:876-8 (2014)

PMID: 25526300

CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection.

Linterman MA,Denton AE,Divekar DP,Zvetkova I,Kane L,Ferreira C,Veldhoen M,Clare S,Dougan G,Espeli M,Smith KG

eLife
3 2050-084X: (2014)

PMID: 25347065

Cellular Plasticity of CD4+ T Cells in the Intestine.

V Brucklacher-Waldert, EJ Carr, MA Linterman

Frontiers in immunology
5 1664-3224:488 (2014)

PMID: 25339956