Compound heterozygosity for Pten and SHIP augments T-dependent humoral immune responses and cytokine production by CD(4+) T cells.
Tight regulation of the phosphatidylinositiol 3-kinase (PI3K) pathway is essential not only for normal immune system development and responsiveness, but also in the prevention of immunopathology. Indeed, unchecked activation of the PI3K pathway in T cells induces lymphoproliferation and systemic autoimmunity. Evaluating the importance of threshold levels of two key PI3K pathway phosphoinositol phosphatases, we previously reported that mice heterozygous for both Pten and SHIP develop a more rapid progression of a lymphoproliferative autoimmune syndrome than do Pten(+\-) mice. Investigating the basis for this difference, we now describe a quantitative and qualitative difference in the antibody responses of C57BL\6 Pten(+\-) SHIP(+\-) mice upon challenge with a T-dependent antigen. Suspecting that this phenotypic difference might be the result, at least in part, of a T-helper cell defect, an in vitro analysis of anti-CD3/interleukin (IL)-2-expanded CD4(+) T cells was performed. After stimulation with anti-CD3, cells from mice heterozygous for both Pten and SHIP exhibited a striking increase in IL-4 secretion (> 10-fold), without a corresponding increase in T helper 2 (Th2) cell numbers being evident by intracellular staining for this cytokine. Modest increases were also seen for both IL-13 and IFN-gamma. Perhaps in keeping with this abnormal in vitro cytokine profile, IgG1 serum levels were significantly elevated in young C57BL\6 Pten(+\-) SHIP(+\-) mice. Thus, the relative levels of Pten and SHIP appear to be key variables in CD4(+) T-cell function, primarily via their ability to regulate IL-4 production.
Moody
J L
JL
Department of Biochemistry and Molecular Biology, and Joint Injury and Arthritis Research Group, University of Calgary, Calgary, Alberta, Canada.
Jirik
F R
FR
D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D017252:CD3 Complex; D016207:Cytokines; D007074:Immunoglobulin G; D018793:Interleukin-13; D025521:Tumor Suppressor Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases