Role of T-cell-associated lymphocyte function-associated antigen-1 in the pathogenesis of experimental colitis.
The beta2 integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18) is important for lymphocyte trafficking and activation as well as recruitment to sites of tissue inflammation. The objective of this study was to assess the role of 'T-cell-associated' LFA-1 in the pathogenesis of chronic colitis in vivo. Transfer of CD4+CD25- T cells isolated from wild-type (wt) mice into immunodeficient recipients [recombinase-activating gene-1-deficient (RAG-1-/-] produced moderate to severe colitis, whereas RAG-1-/- mice injected with CD11a-deficient (CD11a-/-; LFA-1-/-) donor T cells displayed minimal macroscopic and histological evidence of colitis. Surface expression of L-selectin, alpha4, alpha4beta7 and chemokine receptor-7 were similar for wt and CD11a-/- donor T cells. Attenuated disease in the CD11a-/- --> RAG-1-/- animals was associated with decreased numbers of CD4+ T cells in the mesenteric lymph nodes (MLNs), spleen and intestinal lamina propria (LP). In addition, significant reductions in Th1 cytokines were observed following ex vivo stimulation of mononuclear cells obtained from the MLNs and colonic LP. Interestingly, mononuclear cells obtained from the spleens of CD11a-/- --> RAG-1-/- exhibited enhanced pro-inflammatory cytokine production compared with splenocytes obtained from wt --> RAG-1-/- colitic mice. Taken together, our data suggest that T-cell-associated CD11a (LFA-1) expression plays a dual role in the initiation of chronic gut inflammation by facilitating naive T-cell priming/activation and expansion within MLNs and by augmenting pro-inflammatory cytokine production following secondary stimulation by antigen-presenting cells in the colonic interstitium.
Pavlick
Kevin P
KP
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71130-3932, USA.
Ostanin
Dmitry V
DV
Furr
Kathryn L
KL
Laroux
F Stephen
FS
Brown
Carla M
CM
Gray
Laura
L
Kevil
Christopher G
CG
Grisham
Matthew B
MB
D000818:Animals; D015415:Biomarkers; D040881:CD11a Antigen / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D016867:Immunocompromised Host / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008643:Mesentery; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology
D015415:Biomarkers; D040881:CD11a Antigen; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1