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

The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes.
Hill DL, Pierson W, Bolland DJ, Mkindi C, Carr EJ, Wang J, Houard S, Wingett SW, Audran R, Wallin EF, Jongo SA, Kamaka K, Zand M, Spertini F, Daubenberger C, Corcoran AE, Linterman MA

The generation of protective humoral immunity after vaccination relies on the productive interaction between antigen-specific B cells and T follicular helper (Tfh) cells. Despite the central role of Tfh cells in vaccine responses, there is currently no validated way to enhance their differentiation in humans. From paired human lymph node and blood samples, we identify a population of circulating Tfh cells that are transcriptionally and clonally similar to germinal center Tfh cells. In a clinical trial of vaccine formulations, circulating Tfh cells were expanded in Tanzanian volunteers when an experimental malaria vaccine was adjuvanted in GLA-SE but not when formulated in Alum. The GLA-SE-formulated peptide was associated with an increase in the extrafollicular antibody response, long-lived antibody production, and the emergence of public TCRβ clonotypes in circulating Tfh cells. We demonstrate that altering vaccine adjuvants is a rational approach for enhancing Tfh cells in humans, thereby supporting the long-lived humoral immunity that is required for effective vaccines.

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The Journal of experimental medicine, , 1540-9538, , 2019

PMID: 31175140

Heterochronic faecal transplantation boosts gut germinal centres in aged mice.
Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, Linterman MA

Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system; however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer's patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli.

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Nature communications, 10, 2041-1723, 2443, 2019

PMID: 31164642

FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.
Espéli M, Bashford-Rogers R, Sowerby JM, Alouche N, Wong L, Denton AE, Linterman MA, Smith KGC

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.

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Nature communications, 10, 2041-1723, 1970, 2019

PMID: 31036800

Group Members

Latest Publications

The adjuvant GLA-SE promotes human Tfh cell expansion and emergence of public TCRβ clonotypes.

Hill DL, Pierson W, Bolland DJ

The Journal of experimental medicine
1540-9538: (2019)

PMID: 31175140

Heterochronic faecal transplantation boosts gut germinal centres in aged mice.

Stebegg M, Silva-Cayetano A, Innocentin S

Nature communications
10 2041-1723:2443 (2019)

PMID: 31164642

FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.

Espéli M, Bashford-Rogers R, Sowerby JM

Nature communications
10 2041-1723:1970 (2019)

PMID: 31036800

Relative Frequencies of Alloantigen-Specific Helper CD4 T Cells and B Cells Determine Mode of Antibody-Mediated Allograft Rejection.

Alsughayyir J, Chhabra M, Qureshi MS

Frontiers in immunology
9 1664-3224:3039 (2018)

PMID: 30740108

Germinal Center Alloantibody Responses Mediate Progression of Chronic Allograft Injury.

Chhabra M, Alsughayyir J, Qureshi MS

Frontiers in immunology
9 1664-3224:3038 (2018)

PMID: 30728823

Type I interferon induces CXCL13 to support ectopic germinal center formation.

Denton AE, Innocentin S, Carr EJ

The Journal of experimental medicine
1540-9538: (2019)

PMID: 30723095

Data regarding transplant induced germinal center humoral autoimmunity.

Qureshi MS, Alsughayyir J, Chhabra M

Data in brief
22 2352-3409:647-657 (2019)

PMID: 30671513

Germinal center humoral autoimmunity independently mediates progression of allograft vasculopathy.

Qureshi MS, Alsughayyir J, Chhabra M

Journal of autoimmunity
1095-9157: (2018)

PMID: 30528910

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