Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice.
OBJECTIVE
Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich syndrome protein (WASP), a hematopoietic cell-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T cell-mediated colitis in mice with WASP-deficient cells of the innate immune system.


METHODS
Naïve and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2-deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays.


RESULTS
Transfer of unfractionated CD4(+) T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naïve wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared with RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients and associated with reduced numbers of CD103(+) tolerogenic dendritic cells and levels of interleukin-10. Administration of interleukin-10 prevented induction of colitis following transfer of T cells into WRDKO mice.


CONCLUSIONS
Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of interleukin-10, and homeostasis of regulatory T cells.
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: dnguyen3@partners.org.
Deanna D
DD
Nguyen
Harvard Medical School, Boston, Massachusetts; Department of Gastroenterology/Nutrition, Children's Hospital, Boston, Massachusetts.
Marc-Andre
MA
Wurbel
Harvard Medical School, Boston, Massachusetts; Department of Gastroenterology/Nutrition, Children's Hospital, Boston, Massachusetts.
Jeremy A
JA
Goettel
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts.
Michelle A
MA
Eston
Department of Gastroenterology/Nutrition, Children's Hospital, Boston, Massachusetts.
Osub S
OS
Ahmed
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts.
Romela
R
Marin
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Elisa K
EK
Boden
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Eduardo J
EJ
Villablanca
Harvard Medical School, Boston, Massachusetts; Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts.
Helena
H
Paidassi
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Vineet
V
Ahuja
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Hans-Christian
HC
Reinecker
Harvard Medical School, Boston, Massachusetts; Department of Gastroenterology/Nutrition, Children's Hospital, Boston, Massachusetts.
Edda
E
Fiebiger
Harvard Medical School, Boston, Massachusetts; Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts.
Adam
A
Lacy-Hulbert
Harvard Medical School, Boston, Massachusetts; Division of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Bruce H
BH
Horwitz
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
J Rodrigo
JR
Mora
Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Department of Gastroenterology/Nutrition, Children's Hospital, Boston, Massachusetts; Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: scott.snapper@childrens.harvard.edu.
Scott B
SB
Snapper
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D039001:Integrin alpha Chains / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency* / Q000235:genetics
D015703:Antigens, CD; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D039001:Integrin alpha Chains; C499308:Rag2 protein, mouse; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C091367:alpha E integrins; D016753:Interleukin-10