Background/Purpose:

Transforming growth factor-beta inducible gene-h3 (βig-h3) is abundantly expressed in synovial tissues of rheumatoid arthritis (RA) and has a regulatory role in growth, differentiation, adhesion, migration, and survival of cells. Previously, we found that βig-h3 regulates the adhesion and migration of T cells expressing a high level of α5β1 integrin. Therefore, we sought to investigate whether βig-h3 regulates the adhesion of specific T cell subsets selectively and whether it recruits T cells into arthritic tissues differentially according to expression of βig-h3 in a soluble form or in situwithin synovial tissues.

Methods:

T cells were isolated using negative selection kit with MACS. T cell subsets were isolated with antibodies against CD4, CD45RO, and a5 integrin using FACS Aria^TM. Adhesion of T cell subsets was investigated on βig-h3-coated microtitre plates. βig-h3 overexpressing mice were generated by the insertion of hβig-h3 transgene downstream of albumin promotor. βig-h3 deficient mice were also prepared by deleting βig-h3 gene using homologous recombination. Collagen antibody induced arthritis (CAIA) model was prepared. Recruitment of effector T cells was evaluated using in vivo homing assay.

Results: T cells isolated from SF of RA were mostly α5β1^Hi, while most of those from PB of controls were α5β1^Lo. Adhesion of SF T cells on the coated βig-h3 was enhanced compared with normal or RA PB T cells, which was inhibited by the function blocking antibody against α5β1 integrin. RGD peptide, which also binds to αvβ3 integrin, did not block βig-h3-mediated adhesion of T cells, while dhfas-1, a fragment of the 4th fas-1 domain of βig-h3, blocked the adhesion in a dose-dependent manner. The proportion of CD45RO⁺ cells among T cells was increased in the PB and SF of RA compared to PB of controls. Most of the CD45RO⁺ T cells were α5β1^Hi population, while almost all the CD45RO^– T cells were α5β1^Lo population. βig-h3-mediated adhesion were higher in the CD4⁺CD45RO⁺α5^Hi T cells compared with CD4⁺CD45RO⁺α5^Lo and CD4⁺CD45RO^–α5^Lo T cells (0.40 ± 0.03 vs 0.19 ± 0.03 and 0.22 ± 0.02, respectively, P < 0.01). In βig-h3-trasgenic CAIA mice, arthritis severity was efficiently ameliorated compared with control (P < 0.05) and tissue sections revealed a decreased number of infiltrating T cells. In βig-h3 deficient mice, the severity of CAIA was significantly less severe compared to wild type C57BL6/J mice (P < 0.05), which was consistent with reduced histologic scores. To evaluate the role of βig-h3 in T cell recruitment into synovial tissues, in vivo homing of T cells was assessed after adoptive transfer of CSFE-labeled effector T cells. Homing of effector T cells into joint tissue was significantly reduced in βig-h3 deficient CAIA mice compared with that of wild type CAIA mice (P< 0.05).  

Conclusion: The present data indicate that βig-h3 may play a critical role in the regulation of inflammation by the selective recruitment of memory/effector T cells into the synovial tissues of RA through the interaction with α5β1 integrin. These results implicate a soluble βig-h3-based therapeutic strategy for the treatment of inflammatory arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/%ce%b2ig-h3-regulates-the-inflammatory-arthritis-by-mediating-selective-recruitment-of-effectormemory-t-cells/