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.
During the process of aging, the fraction of CD4+ T Cells with a naive phenotype, that is,
Pgp-1- CD45RBHighMEL-14+, decreases in favor of CD4+ T memory cells. Total CD4+ T
cells from aged mice displayed a diminished calcium response to anti-CD3 and even
ionomycin as compared to the cells from young mice, and this was related to the
changed composition of the CD4+ T-cell population. Regardless the age of the donor
mice, naive CD4+ T cells effectively increased intracellular calcium, whereas memory
CD4+ T cells were impaired in this regard. In addition, a heterogeneity in the
differentiation stage of the naive CD4+ T cells was shown by the observation that
calcium mobilization in naive CD4+ T cells from young mice was more profound than
that in their aged counterparts. These data thus indicate that during the acquisition of a
memory phenotype, murine CD4+ T cells lose the capacity to increase intracellular
calcium, which in turn may be responsible for the decreased level of IL-2 production by
these cells.
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