Association of CD45(dim)VLA-4 (+) cells with the NKT cell lineage and their selective expression of IL-13, IP-15, and CCR3 transcripts.
BACKGROUND
Estrogen (E2) was shown to prevent experimental autoimmune encephalomyelitis (EAE) and to produce a novel population of regulatory CD45(dim)VLA-4(+) cells. Although their appearance was dependent upon an elevated hormonal level, E2 was not required for their production, as they also were induced by immunization with Mycobacterium tuberculosis as a component of complete Freund's adjuvant.


METHODS
Molecular techniques, including ribonuclease protection assays and quantitative RT-PCR, were used to provide further characterization of CD45(dim)VLA-4(+) cells. Moreover, we determined the developmental requirements of the CD45(dim)VLA-4(+) cells using genetically modified mice and extensive flow cytometry analysis.


RESULTS
Characterization of CD45(dim)VLA-4(+) mRNA profile revealed highly elevated levels of CD16, CD44, CCR3, IP-15, and IL-13 transcripts compared with their CD45(high)VLA-4(+) counterparts. Furthermore, we found up-regulation of anti-apoptotic bcl-w and bcl-xl genes and transcripts encoding the TCRalpha and CD8alpha homodimer. The production of CD45(dim)VLA-4(+) cells was evident in nude mice and in MHC class II- and beta2-microglobulin, but not in CD1-deficient mice, suggesting a crucial role for CD1 in their induction.


CONCLUSIONS
These findings suggest that CD45(dim)VLA-4(+) cells might resemble natural killer T cells and imply possible roles for IL-13 and IP-15 in the protective function of CD45(dim)VLA-4(+) cells. A better understanding of how these cells, also occurring naturally during pregnancy, suppress the harmful immune response of EAE may lead to novel therapeutic approaches to combat multiple sclerosis and other autoimmune diseases.
Matejuk
Agata
A
Pathology Department, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098, USA. matejuka@ohsu.edu
Afentoulis
Michael
M
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage; D004958:Estradiol / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D005786:Gene Expression Regulation; D016130:Immunophenotyping; D039041:Integrin alpha4beta1 / Q000032:analysis*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis*; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D018949:Antigens, CD1; D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; C101155:Bcl2l2 protein, mouse; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C515351:Ccr3 protein, mouse; C488102:IP15 protein, mouse; D039041:Integrin alpha4beta1; D018793:Interleukin-13; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D051020:bcl-X Protein; D004958:Estradiol; D005620:Freund's Adjuvant; D017493:Leukocyte Common Antigens