Differential regulation of VLA-2 expression on Th1 and Th2 cells: a novel marker for the classification of Th subsets.
We found that T(h)1 cells derived from ovalbumin (OVA)-specific TCR transgenic (DO11.10) mice showed significantly higher levels of VLA-2 (CD49b/CD29) expression than T(h)2 cells. In the early days (until 6 days) during induction of T(h)1 or T(h)2 cells, the expression of VLA-2 was gradually increased on both T(h) subsets. Thereafter, VLA-2 expression was further up-regulated on T(h)1 cells until 13 days, while a significant decrease of VLA-2 was observed in T(h)2 cells, resulting in a marked difference of expression at day 13. Up-regulation of VLA-2 on T(h)1 cells was not impaired in IFN-gamma(-/-) T(h) cells nor blocked by anti-IL-12 mAb treatment on wild-type T(h) cells, suggesting that up-regulation of VLA-2 on T(h)1 cells occurs in an IFN-gamma- and IL-12-independent manner. In contrast, T(h) cells cultured under IL-4-depleted T(h)2 conditions abrogated the down-regulation of VLA-2 expression, suggesting that down-regulation of VLA-2 expression on T(h)2 cells was dependent on IL-4. The finding that STAT6(-/-) T(h)2 cells did not show any down-regulation of VLA-2 expression and expressed the same levels of VLA-2 as T(h)1 cells indicated a critical role for the IL-4 receptor/STAT6 signaling pathway in IL-4-dependent down-regulation of VLA-2 on T(h)2 cells. Stimulation of T(h)1 cells by VLA-2 ligands such as collagen type I or agonistic mAb provided co-stimulation for anti-CD3 mAb-induced IFN-gamma production. However, these ligations had little effect on the IL-4 production of T(h)2 cells. Together, these results indicate that VLA-2 is a novel functional marker that dissociates T(h)1 from T(h)2 cells, and thus might be useful for therapeutic monitoring of T(h)1-dependent immune diseases such as rheumatoid arthritis or Crohn's disease.
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Kotaro
K
Sasaki
Takemasa
T
Tsuji
Takafumi
T
Jinushi
Jyunko
J
Matsuzaki
Takeshi
T
Sato
Kenji
K
Chamoto
Yuji
Y
Togashi
Toshiaki
T
Koda
Takashi
T
Nishimura
D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D038982:Integrin alpha2beta1 / Q000096:biosynthesis* / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000494:pharmacology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000145:classification* / Q000187:drug effects / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification* / Q000187:drug effects / Q000378:metabolism
D015415:Biomarkers; D038982:Integrin alpha2beta1; D015847:Interleukin-4; D007371:Interferon-gamma