The Involvement of the Intestinal Microflora in theExpansion of CD4⁺ T Cells with a‐Naive Phenotype inthe Periphery

Abstract

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.

Environmental and Intrinsic Factors Lead to Antigen Unresponsiveness in CD4+ Recent Thymic Emigrants from Aged Mice

“…Aged RTE have a cell surface phenotype that is characteristic of the aged CD4 T cell pool, while RTE in young animals have a uniformly naive phenotype. Some component of the age-associated phenotype shift in CD4 T cells is likely to be independent of exposure to cognate Ag, because aged mice housed in germ-free conditions exhibit a shift to predominance of "memory" phenotype cells (3). It is unlikely that the up-regulation of CD44 in aged RTE is a result of antigenic exposure, because it is observed in RTE from both TCR Tg and polyclonal inbred mice.…”

“…These memory cells respond more rapidly to challenge and have less stringent requirements for Ag and costimulatory factors than naive CD4 cells. Advancing age leads to a predominance of CD44 high CD62L low cells that are thought to accumulate as a result of a lifetime of exposure to Ags (1, 2), although some "memory" phenotype cells that arise with age may also be derived through homeostatic division or other Ag independent age-related changes, because they develop in TCR transgenic cells that have not been exposed to cognate Ag as well as in mice raised in germfree environments (3). Defects in response to Ag have been described in both CD44 low CD62L…”

Thymus-Dependent Memory Phenotype CD8 T Cells in Naive B6.H-2Kb−/−Db−/− Animals Mediate an Antigen-Specific Response against Listeria monocytogenes

“…However, memory phenotype CD4 cells are also found in naive mice maintained under germfree conditions, suggesting that their development is not foreign Ag dependent (51). Because T cells from male anti-H-Y TCR-transgenic mice can develop extrathymically and display memory markers, it is possible that the development of memory phenotype CD8 T cells in naive mice is driven by the interaction of the ␣␤TCR with self-Ags and developed extrathymically (13,18,19).…”

Bacteria–bacteria interactions within the microbiota of the ancestral metazoan Hydra contribute to fungal resistance

“…The intestinal microbiota can stimulate stem cell turnover (Jones et al, 2013), gut development (Rawls et al, 2004) and facilitate nutrient supply by breakdown of complex carbohydrates or synthesis of essential amino acids (Sandströ m et al, 2000;Douglas et al, 2001;Yatsunenko et al, 2012). Furthermore, commensal microbes are able to stimulate fundamental aspects of innate and adaptive immunity such as T-cell maturation, production of IgA, mucus secretion and induction of antimicrobial peptides (Dobber et al, 1992;Mazmanian et al, 2005;Weiss et al, 2012).…”