γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice.
OBJECTIVE
Intraepithelial lymphocytes that express the γδ T-cell receptor (γδ IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether γδ IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection.


METHODS
Salmonella typhimurium or Toxoplasma gondii were administered to knockout (KO) mice lacking either the T cell receptor δ chain (Tcrd) or CD103, or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of green fluorescent protein (GFP)-tagged γδ T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of γδ IEL migration on early pathogen invasion and chronic systemic infection.


RESULTS
Morphometric analyses of intravital video microscopy data showed that γδ IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hour, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO γδ T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient γδ T cells, whereas invasion in CD103 KO mice, which have increased migration of γδ T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of γδ T-cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient γδ IELs, relative to those with wild-type or CD103 KO γδ IELs.


CONCLUSIONS
In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to γδ IEL surveillance and immediate host defense. γδ IEL occludin is required for early surveillance that limits systemic disease.
Department of Pathology, The University of Chicago, Chicago, Illinois.
Karen L
KL
Edelblum
Department of Pathology, The University of Chicago, Chicago, Illinois.
Gurminder
G
Singh
Department of Pathology, The University of Chicago, Chicago, Illinois.
Matthew A
MA
Odenwald
Department of Pathology, The University of Chicago, Chicago, Illinois.
Amulya
A
Lingaraju
Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, Illinois; Department of Pediatrics, The University of Chicago, Chicago, Illinois.
Kamal
K
El Bissati
Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, Illinois; Department of Pediatrics, The University of Chicago, Chicago, Illinois.
Rima
R
McLeod
Department of Medicine, The University of Chicago, Chicago, Illinois; Section of Pulmonary and Critical Care, The University of Chicago, Chicago, Illinois. Electronic address: asperlin@medicine.bsd.uchicago.edu.
Anne I
AI
Sperling
Department of Pathology, The University of Chicago, Chicago, Illinois; Department of Medicine, The University of Chicago, Chicago, Illinois. Electronic address: jturner@bsd.uchicago.edu.
Jerrold R
JR
Turner
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D018988:Bacterial Translocation; D016026:Bone Marrow Transplantation; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D039001:Integrin alpha Chains / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062793:Occludin / Q000172:deficiency / Q000187:drug effects; D010539:Permeability; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000187:drug effects / Q000378:metabolism*; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity*; D013997:Time Factors; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D018183:Transplantation Chimera; D014774:Virulence
D015703:Antigens, CD; D039001:Integrin alpha Chains; D062793:Occludin; C568986:Ocln protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; C091367:alpha E integrins
Host Defense; Intestinal Epithelium; T cell; Tight Junction