T cell-associated α4β7 but not α4β1 integrin is required for the induction and perpetuation of chronic colitis.
Anti-adhesion therapies that target α(4) integrins (e.g., natalizumab) are thought to work by blocking T-cell recruitment to the intestinal tissues in patients with Crohn's disease (CD); however, little direct evidence is available to confirm this contention. We wished to evaluate the importance of T cell-associated α(4) integrins in a chronic colitis model in mice and to determine the effect of natalizumab treatment on intestinal tissue T-cell accumulation in human CD. Adoptive transfer of T cells lacking α(4) (α(4)(-/-)) but not β(1) integrin into immunodeficient mice produced significantly attenuated disease. This was correlated with reduced numbers of colon CD4 T cells compared with the control mice; however, tissue distribution of T helper type 1 (Th1) and T helper type 17 (Th17) cells and regulatory T cells (Tregs) was not affected by the lack of α(4). Furthermore, α(4)(-/-) T cells demonstrated defective homing to the chronically inflamed small intestines and colons. Finally, patients treated with natalizumab showed significant reduction in mucosal CD4 T cells and no skewing in the foxp3(+) Treg or T-bet(+)Th1 fractions thereof. These results demonstrate a direct role for T cell-associated α(4)β(7) but not α(4)β(1) integrins during initiation and perpetuation of chronic colitis. Moreover, our data demonstrated that natalizumab treatment reduced mucosal CD4 T-cell accumulation in CD patients.
Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
E
E
Kurmaeva
Translational Research Program, Benaroya Research Institute, Seattle, Washington, USA.
J D
JD
Lord
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
S
S
Zhang
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
J R
JR
Bao
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
C G
CG
Kevil
Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
M B
MB
Grisham
Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
D V
DV
Ostanin
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology*; D039641:Integrin beta Chains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout
D039041:Integrin alpha4beta1; D039641:Integrin beta Chains; C091368:integrin beta7