The involvement of the intestinal microflora in the expansion of CD4+ T cells with a naive phenotype in the periphery.
It is well known that immune reactivity declines with age. Recently, we demonstrated that the age-related decrease in IL-2 production by CD4+ T cells was accompanied by an increased production of IL-4 and interferon-gamma (IFN-gamma). This age-related shift in the profile of lymphokine production was related to phenotypic changes within the CD4+ T-cell subset, that is, a decrease in the percentage of CD45RB++ CD4+ T cells and an increase in the percentage of Pgp-1+ CD4+ T cells. To study whether these age-related changes were due to previous antigenic exposure, we performed a phenotypic and functional analysis on splenic CD4+ T cells isolated from individual germ-free (GF), specific pathogen-free (SPF), and clean conventional (CC) mice. Interestingly, the total number of splenic CD4+ T cells in GF mice was twofold lower as compared to age-matched SPF or CC mice, regardless whether mice were analyzed at young (10 weeks) or at advanced age (13-14 months). Unexpectedly, the phenotypic composition of the CD4+ T-cell subset was comparable in the GF, SPF, and CC mice as determined by the expression of CD45RB and Pgp-1, indicating that CD4+ T cells with a naive phenotype (CD45RB++ Pgp-1-) were not enriched in GF mice. Moreover, at an age of 13-14 months, CD4+ T cells from GF mice frequently produced more IL-4 and IFN-gamma than their CC counterparts. These lymphokine data showed, therefore, that a relatively high proportion of CD4+ T cells with a memory phenotype can also be defined in GF mice on the basis of their function. The contamination of GF mice with a colonization resistant factor (CRF flora) resulted in twofold higher numbers of splenic CD4+ T cells. Surprisingly, not only CD4+ T cells with a memory phenotype (CD45RB-/+ Pgp-1++) had expanded, but also CD4+ T cells with a naive (CD45RB++ Pgp-1-) phenotype. Our results, therefore, strongly suggest that the expansion of naive CD4+ T cells in the periphery is mediated by the intestinal microflora.
Dobber
R
R
Section of Immunology, Institute of Ageing and Vascular Research TNO, Leiden, The Netherlands.
Hertogh-Huijbregts
A
A
Rozing
J
J
Bottomly
K
K
Nagelkerken
L
L
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D005260:Female; D005856:Germ-Free Life / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000096:biosynthesis / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D017493:Leukocyte Common Antigens; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D010641:Phenotype; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis / Q000276:immunology; D013047:Specific Pathogen-Free Organisms / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure
D015703:Antigens, CD; D015704:CD4 Antigens; D006649:Histocompatibility Antigens; D016201:Receptors, Lymphocyte Homing; D017493:Leukocyte Common Antigens