Loss of Src homology region 2 domain-containing protein tyrosine phosphatase-1 increases CD8+ T cell-APC conjugate formation and is associated with enhanced in vivo CTL function.
Extensive evidence has been accumulated to implicate the intracellular protein tyrosine phosphatase, Src homology region 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), as a negative regulator of TCR-signaling thresholds. Specifically, T cells from the SHP-1-deficient mouse, motheaten, exhibit a hyperproliferative phenotype when activated by cognate peptide-pulsed APCs. However, the cellular basis for this phenotype has not been fully explained. Using the intracellular fluorescent dye, CFSE, we show that a greater proportion of motheaten vs control naive CD8(+) T cells undergo cell division when activated by peptide-pulsed APCs. Furthermore, there is a greater likelihood of TCRs on SHP-1-deficient vs control T cells binding to peptide/MHC ligands on APCs when using TCR down-regulation as an indirect measure of TCR engagement. In addition, T cell-APC conjugate assays provide direct evidence that a greater proportion of SHP-1-deficient T cells are capable of forming stable conjugates with APCs and this may explain, at least in part, their hyperproliferative response to TCR-triggered stimulation. The physiological relevance of the combined in vitro observations is demonstrated by the significantly enhanced in vivo expansion and CTL capacity generated in mice receiving adoptively transferred SHP-1-deficient naive CD8(+) T cells when compared with control T cells.
Sathish
Jean G
JG
Section of Infection and Immunity, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
Dolton
Garry
G
Leroy
Frances G
FG
Matthews
R James
RJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002448:Cell Adhesion / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D018920:Coculture Techniques; D015536:Down-Regulation; D005353:Fibronectins / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D010455:Peptides / Q000494:pharmacology; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D018909:src Homology Domains
D000906:Antibodies; D005353:Fibronectins; C090509:Icam1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6