The ability of CD4+ T cells from CBA/Rij mice to produce interleukin (IL) 2 after stimulation with anti-CD3, concanavalin A, or the combination of phorbol 12-myristate 13-acetate and ionomycin declines during aging. This phenomenon was accompanied by an increased production of IL 4 and interferon-gamma. These age-related changes in lymphokine production correlated with the decrease in the percentage of CD45RBhi CD4+ T cells from about 80% in 2-month-old to about 40% in 27-month-old mice. This phenotypic shift was responsible for the decline in IL 2 production, because in young and in old mice CD45RBhi CD4+ T cells were more potent IL 2 producers than CD45RBlo cells. Moreover, old CD45RBhi CD4+ T cells produced less IL 2 than their young counterparts. Proliferative responses by T cells from old mice were lower than those of young mice, regardless whether the cultures were supplemented with IL 2, IL 4 or both lymphokines. As far as CD4+ T cells were concerned, this hyporesponsiveness was found in the CD45RBlo as well as in the CD45RBhi CD4+ T cell population.
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-γ,(IFN-γ). 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-γ, 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.
Aging is accompanied by an increased fraction of memory CD4+ T cells. Despite the fact that human memory cells have been reported to produce high levels of IL-2, studies in mice and man indicate an age-related decline in IL-2 production. In the present study, we examined whether these conflicting results depend on the activation pathway employed in a comparison of phenotypically distinct CD4+ T cells from young and aged mice. Our data indicate an age-related decline in IL-2 production by CD4+ T cells when the cells were stimulated with concanavalin A in the presence of accessory cells or the combination of immobilized anti-CD3 and soluble anti-CD28. However, when CD4+ T cells were only stimulated with immobilized anti-CD3, an age-related increase in IL-2 production was observed. This age-related increase in IL-2 could be attributed to the ability of CD4+ T cells from aged mice to produce IL-4 on this stimulation, since anti-IL-4 inhibited the IL-2 production in these cultures to levels found with cells from young mice. The addition of exogenous IL-4 greatly enhanced the IL-2 production of CD4+ T cells from young mice to levels far beyond that of the aged counterparts, emphasizing the dominant role of IL-4 in the induction of IL-2 stimulated with immobilized anti-CD3. No differences were observed in the activation requirements of Mel14- CD4+ T cells from young and aged mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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