CD4(+) and CD8(+) T cells kill intracellular Mycobacterium tuberculosis by a perforin and Fas/Fas ligand-independent mechanism.
Cytotoxic effector phenotype and function of MHC-restricted Mycobacterium tuberculosis (MTB)-reactive CD4(+) and CD8(+) T lymphocytes were analyzed from healthy tuberculin skin test-positive persons. After stimulation in vitro with MTB, both CD4(+) and CD8(+) T cells up-regulated mRNA expression for granzyme A and B, granulysin, perforin, and CD95L (Fas ligand). mRNA levels for these molecules were greater for resting CD8(+) than CD4(+) T cells. After MTB stimulation, mRNA levels were similar for both T cell subsets. Increased perforin and granulysin protein expression was confirmed in both in CD4(+) and CD8(+) T cells by flow cytometry. Both T cell subsets lysed MTB-infected monocytes. Biochemical inhibition of the granule exocytosis pathway in CD4(+) and CD8(+) T cells decreased cytolytic function by >90% in both T cell subsets. Ab blockade of the CD95-CD95L interaction decreased cytolytic function for both T cell populations by 25%. CD4(+) and CD8(+) T cells inhibited growth of intracellular MTB in autologous monocytes by 74% and 84%, respectively. However, inhibition of perforin activity, the CD95-CD95L interaction, or both CTL mechanisms did not affect CD4(+) and CD8(+) T cell mediated restriction of MTB growth. Thus, perforin and CD95-CD95L were not involved in CD4(+) and CD8(+) T cell mediated restriction of MTB growth.
Canaday
D H
DH
Division of Infectious Diseases, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, OH 44106, USA. dxc44@cwru.edu
Wilkinson
R J
RJ
Li
Q
Q
Harding
C V
CV
Silver
R F
RF
Boom
W H
WH
D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D001770:Blood Bactericidal Activity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D053804:Granzymes; D006801:Humans; D066298:In Vitro Techniques; D008285:Major Histocompatibility Complex; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C075005:GNLY protein, human; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D019014:fas Receptor; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human