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

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.

+ View Abstract

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, Mallik M, Ali JM, Gamper I, Moseley EL, Peacock S, Kosmoliaptsis V, Goddard MJ, Linterman MA, Motallebzadeh R, Pettigrew GJ

Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. Here, we examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR). An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient () C57BL/6 recipients against donor H-2K MHC class I alloantigen was provided by adoptively transferred "TCR75" CD4 T cells that recognize processed H-2K allopeptide via the indirect-pathway. Transfer of large numbers (5 × 10) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2K humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) recipients, suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to recipients resulted in eventual BALB/c heart allograft rejection (MST 20 days). Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c heart grafts were predominantly generated by extrafollicular foci: splenic germinal center (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of TCR75 CD4 T cells that are genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (10), although long-lasting, did not have a discernible extrafollicular component, and grafts were rejected much more slowly (MST 50 days). By modeling antibody responses to Hen Egg Lysozyme protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favors development of the extrafollicular response, whereas GC activity is favored by a relatively high ratio of B cells. In summary, a relative abundance of helper CD4 T cells favors development of strong extrafollicular alloantibody responses that mediate acute humoral rejection, without requirement for GC activity. This work is composed of two parts, of which this is Part I. Please read also Part II: Chhabra et al., 2019.

+ View Abstract

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, Mallik M, Ali JM, Gamper I, Moseley EL, Peacock S, Kosmoliaptsis V, Goddard MJ, Linterman MA, Motallebzadeh R, Pettigrew GJ

Different profiles of alloantibody responses are observed in the clinic, with those that persist, often despite targeted treatment, associated with poorer long-term transplant outcomes. Although such responses would suggest an underlying germinal center (GC) response, the relationship to cellular events within the allospecific B cell population is unclear. Here we examine the contribution of germinal center (GC) humoral alloimmunity to chronic antibody mediated rejection (AMR). A murine model of chronic AMR was developed in which T cell deficient () C57BL/6 recipients were challenged with MHC-mismatched BALB/c heart allografts and T cell help provided by reconstituting with 10 "TCR75" CD4 T cells that recognize self-restricted allopeptide derived from the H-2K MHC class I alloantigen. Reconstituted recipients developed Ig-switched anti-K alloantibody responses that were slow to develop, but long-lived, with confocal immunofluorescence and flow cytometric characterization of responding H-2K-allospecific B cells confirming persistent splenic GC activity. This was associated with T follicular helper (T) cell differentiation of the transferred TCR75 CD4 T cells. Heart grafts developed progressive allograft vasculopathy, and were rejected chronically (MST 50 days), with explanted allografts displaying features of humoral vascular rejection. Critically, late alloantibody responses were abolished, and heart grafts survived indefinitely, in recipients reconstituted with TCR75 CD4 T cells that were genetically incapable of providing T cell function. The GC response was associated with affinity maturation of the anti-K alloantibody response, and its contribution to progression of allograft vasculopathy related principally to secretion of alloantibody, rather than to enhanced alloreactive T cell priming, because grafts survived long-term when B cells could present alloantigen, but not secrete alloantibody. Similarly, sera sampled at late time points from chronically-rejecting recipients induced more vigorous donor endothelial responses than sera sampled earlier after transplantation. In summary, our results suggest that chronic AMR and progression of allograft vasculopathy is dependent upon allospecific GC activity, with critical help provided by T cells. Clinical strategies that target the T cell subset may hold therapeutic potential. This work is composed of two parts, of which this is Part II. Please read also Part I: Alsughayyir et al., 2019.

+ View Abstract

Frontiers in immunology, 9, 1664-3224, 3038, 2018

PMID: 30728823

Group Members

Latest Publications

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

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