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Identification of T cell autoepitopes that cross-react with the C-terminal segment of the M protein of group A
S Pruksakorn1, B Currie, E Brandt
1Molecular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
Abstract:
Rheumatic fever (RF) follows a throat infection with different M-serotypes of beta-hemolytic group A streptococci (GAS) and can affect different tissues, predominantly the heart. It is thought to be an autoimmune illness. Although histological examination of affected heart shows an infiltrate consisting mainly of T cells, antigens or epitopes that could be putative targets of autoimmune T cells have not been identified. We have examined the T cell response to the conserved C-terminal region of the M protein--a streptococcal surface coiled-coil protein which is the target of opsonic antibodies and antibodies which cross-react with human heart tissue. Australian Aborigine, Caucasian and Thai patients, controls and mice were studied to define regions of the protein immunogenic for T cells, and T cell lines and clones were tested for cross-reactivity to myosin as well as an extract of RF-diseased mitral heart valve. Murine (B10, B10.D2, B10.BR) M peptide-specific T cells were often cross-reactive for other M peptides but did not cross-react with human heart antigens. Patients with RF or other heart diseases, or control subjects exposed more commonly to GAS were more likely to have T cell responses to the M protein, with many regions of the C-terminus being recognized. T cell lines and a clone specific for different M peptides were generated from five donors. Cross-reactivity could be shown between different M peptides, but unlike murine M peptide-specific T cells three of the human T cell lines reacted strongly to peptides representing homologous regions of cardiac and skeletal muscle myosins, and two of these lines also responded to porcine myosin and an extract of human rheumatic mitral valve. However, these last two lines were derived from a normal donor without history of RF or other heart disease. Our data demonstrate that regions of the M protein, including regions that are being considered as subunit vaccines, have the potential to stimulate pre-existing heart cross-reactive T cells, but that the ability of such T cells to cross-react (as measured in vitro) is not in itself sufficient to lead to disease.
Insights
Rheumatic fever (RF) may involve autoimmune T cells targeting heart tissue. The M protein from group A streptococci (GAS) can stimulate these T cells, but cross-reactivity alone doesn't cause disease.
Area of Science:
- Immunology
- Cardiology
- Microbiology
Background:
- Rheumatic fever (RF) is an autoimmune condition following group A streptococci (GAS) throat infections, primarily affecting the heart.
- Histological analysis of affected heart tissue reveals T cell infiltrates, but specific autoimmune targets remain unidentified.
- The M protein of GAS is a surface protein targeted by opsonic antibodies and antibodies that cross-react with human heart tissue.
Purpose of the Study:
- To investigate T cell responses to the M protein of GAS, focusing on its conserved C-terminal region.
- To identify specific epitopes within the M protein that elicit T cell responses.
- To assess the cross-reactivity of these T cells with human cardiac antigens, particularly myosin and heart valve extracts.
Main Methods:
- Studied T cell responses to M protein peptides in Australian Aborigine, Caucasian, and Thai patients, controls, and mice.
- Generated and tested murine and human T cell lines and clones for cross-reactivity against M peptides, myosin, and rheumatic heart valve extracts.
- Utilized various mouse strains (B10, B10.D2, B10.BR) for in vivo and in vitro analysis.
Main Results:
- Murine T cells specific to M peptides showed cross-reactivity with other M peptides but not human heart antigens.
- Human T cells from RF patients and controls exposed to GAS frequently responded to M protein C-terminal regions.
- Three human T cell lines demonstrated strong cross-reactivity with myosin homologous regions; two also reacted to porcine myosin and human rheumatic mitral valve extract, even from a healthy donor.
Conclusions:
- Certain regions of the M protein, including potential vaccine targets, can activate pre-existing T cells that cross-react with heart tissue.
- In vitro cross-reactivity of T cells with cardiac antigens is not sufficient to cause rheumatic fever or heart disease.
- The study identifies potential autoimmune targets in RF and highlights the complexity of T cell-mediated autoimmunity.