Coexpression of CCR5 and IL-2 in human genital but not blood T cells: implications for the ontogeny of the CCR5+ Th1 phenotype.
Memory T cells that home to inflamed tissues typically express the beta-chemokine receptor CCR5 and exhibit a Th1 cytokine profile. The migration of these cells into the genital tract following antigenic exposure has particular relevance to acquisition of HIV-1 infection, because CCR5 functions as the coreceptor for most sexually transmitted HIV-1 strains. We recently established methodology to purify and culture mononuclear cells from the female reproductive tract, and here we analyzed the phenotype, CCR5 expression, and cytokine production of cervicovaginal T cells in up to 16 donors. The proportion of mucosal T cells expressing CCR5 was markedly expanded as compared with peripheral blood (mean 88% vs 24% in 13 donors), but the receptor density on individual CCR5+ T cells was only slightly increased (mean 5837 vs 4191 MEPE (molecules of equivalent PE) units in 6 of 7 donors). Intracellular costaining for IL-2, IFN-gamma, IL-4, and IL-5 revealed a Th1-type pattern in cervical T cells, with significantly higher percentages of IL-2- and IFN-gamma-producing T cells in the mucosa than in blood (mean 67% vs 29%). Coexpression of surface CCR5 with intracellular IL-2 and IFN-gamma was observed only among T cells in the mucosa, but not among those in circulation. Thus, we postulate that T cell homing to the genital mucosa leads to differentiation into the combined CCR5+ Th1 phenotype. Moreover, the predominance of CCR5+ Th1-type T cells in normal cervical mucosa provides targets accessible for the efficient transmission of macrophage-tropic HIV-1 variants in women following sexual exposure.
Hladik
F
F
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Lentz
G
G
Delpit
E
E
McElroy
A
A
McElrath
M J
MJ
D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000097:blood; D002469:Cell Separation; D002584:Cervix Uteri / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000097:blood; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000097:blood; D009092:Mucous Membrane / Q000166:cytology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000097:blood; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000097:blood; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis / Q000097:blood; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014621:Vagina / Q000166:cytology / Q000378:metabolism*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007371:Interferon-gamma; D007376:Interleukin-2; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019713:Receptors, CCR5; D016201:Receptors, Lymphocyte Homing; D000099192:CD69 Antigens