PTPN22 controls the germinal center by influencing the numbers and activity of T follicular helper cells.
A single nucleotide polymorphism in PTPN22 (R620W), which encodes the Lyp tyrosine phosphatase, has been linked to a number of autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Studies in PTPN22 knockout (KO) mice and in mice expressing the mouse homolog of the pro-autoimmune allele, PEP(R619W), have reported increased germinal center activity and enhanced Ab production. In this article, we present findings that explain the basis for increased germinal center activity in PTPN22 mutant mice. As compared with their wild type equivalents, T follicular helper cells from PTPN22 KO mice proliferate and accumulate to a greater extent, and exhibit enhanced production of IL-21. The follicular regulatory T cells in PTPN22 KO mice do not expand to effectively regulate these T follicular helper cells, resulting in an increase in B cell numbers and Ab production. This is evident in the KBxN mouse model of arthritis in which PTPN22 deficiency results in increased severity of disease. Our findings demonstrate the importance of cell type-specific PTPN22 activity on regulation of Ab production.
Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037.
Christian J
CJ
Maine
Kristi
K
Marquardt
Jocelyn
J
Cheung
Linda A
LA
Sherman
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001168:Arthritis / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D005353:Fibronectins; D020022:Genetic Predisposition to Disease; D018858:Germinal Center / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21
D005353:Fibronectins; D007378:Interleukins; C470100:PeP protein, mouse; D011506:Proteins; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse; D000098546:Interleukin-21