Induction of a regulatory phenotype in human CD4+ T cells by streptococcal M protein.
Regulatory T cells (Tregs) participate in the control of the immune response. In the human system, an IL-10-secreting, T regulatory type 1 cell (Tr1)-like subset of Tregs can be induced by concurrent cross-linking of the TCR and CD46 on naive CD4(+) T cells. Because many viral and bacterial pathogens, including the major human pathogen Streptococcus pyogenes, bind to CD46, we asked whether this bacterium can directly induce Tr1-like cells through the streptococcal ligand for CD46, the M protein. The M5 and M22 proteins were found to induce T cells to develop into the IL-10-producing Tr1-like phenotype. Moreover, whole M5-expressing bacteria, but not isogenic M-negative bacteria, led to proliferation and IL-10 secretion by T cells. The interaction between the M5 protein and T cells was dependent on CD46 and the conserved C repeat region of M5. Supernatants derived from T cells stimulated with M proteins or M protein-expressing bacteria suppressed bystander T cell proliferation through IL-10 secretion. In addition, activation of CD46 through streptococcal M protein induced the expression of granzyme B, providing a second means for these cells to regulate an immune response. These findings suggest that binding to CD46 and exploiting its signaling pathway may represent a strategy employed by a number of important human pathogens to induce directly an immunosuppressive/regulatory phenotype in T cells.
Graduate Program in Immunology, Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jeffrey D
JD
Price
Jessica
J
Schaumburg
Charlotta
C
Sandin
John P
JP
Atkinson
Gunnar
G
Lindahl
Claudia
C
Kemper
D000942:Antigens, Bacterial / Q000502:physiology*; D015703:Antigens, CD / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000502:physiology*; D024201:Bystander Effect / Q000276:immunology; D002352:Carrier Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002474:Cell-Free System / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic; D053804:Granzymes; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000502:physiology; D012697:Serine Endopeptidases / Q000096:biosynthesis; D013297:Streptococcus pyogenes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D020298:U937 Cells
D000942:Antigens, Bacterial; D015703:Antigens, CD; D001425:Bacterial Outer Membrane Proteins; C497857:CD46 protein, human; D002352:Carrier Proteins; D016207:Cytokines; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; C014689:streptococcal M protein; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases