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

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, Pierson W, Ribeiro F, Romão VC, Pires AR, da Silva SL, Fonseca JE, Sousa AE, Linterman MA, Graca L

Germinal center (GC) responses are controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue Tfh cells has been established, the relationship between blood and tissue Tfr cells defined as CXCR5(+)Foxp3(+) T cells remains elusive. We found that blood Tfr cells are increased in Sjögren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood Tfr cells correlated with humoral responses, they lack full B cell-suppressive capacity, despite being able to suppress T cell proliferation. Blood Tfr cells have a naïve-like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell-deficient patients. Therefore, blood CXCR5(+)Foxp3(+) T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating Tfr cells.

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Science immunology, 2, 2470-9468, , 2017

PMID: 28802258

Signals that drive T follicular helper cell formation.
Webb LMC, Linterman MA

T follicular helper (TFH) cells are a distinct type of CD4+ T cell specialized in providing help to B cells during the germinal center (GC) reaction. As such, they are critical determinants of the quality of an antibody response following antigen challenge. Excessive production of TFH cells can result in autoimmunity whilst too few can result in inadequate protection from infection. Hence, their differentiation and maintenance must be tightly regulated to ensure appropriate, but limited, help to B cells. Unlike the majority of other CD4+ T cell subsets, TFH cell differentiation occurs in three phases defined by their anatomical location. During each phase of differentiation the emerging TFH cells express distinct patterns of coreceptors which work together with the T cell receptor (TCR) to drive TFH differentiation. These signals provided by both TCR and coreceptors during TFH differentiation alter proliferation, survival, metabolism, cytokine production and transcription factor expression. This review will discuss how engagement of TCR and coreceptors work together to shape the formation and function of TFH cells. This article is protected by copyright. All rights reserved.

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Immunology, , 1365-2567, , 2017

PMID: 28628194

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Keywords

ageing
follicular helper cells
follicular regulatory cells
germinal response
t cells

Group Members

Latest Publications

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

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