Phenotypic and clonal stability of antigen-inexperienced memory-like T cells across the genetic background, hygienic status, and aging

Abstract

Antigen-inexperienced memory-like T (AIMT) cells are functionally unique T cells representing one of the two largest subsets of murine CD8+ T cells. However, differences between laboratory inbred strains, insufficient data from germ-free mice, a complete lack of data from feral mice, and unclear relationship between AIMT cells formation during aging represent major barriers for better understanding of their biology. We performed a thorough characterization of AIMT cells from mice of different genetic background, age, and hygienic status by flow cytometry and multi-omics approaches including analyses of gene expression, TCR repertoire, and microbial colonization. Our data showed that AIMT cells are steadily present in mice independently of their genetic background and hygienic status. Despite differences in their gene expression profiles, young and aged AIMT cells originate from identical clones. We identified that CD122 discriminates two major subsets of AIMT cells in a strain-independent manner. Whereas thymic CD122LOW AIMT cells (innate memory) prevail only in young animals with high thymic IL-4 production, peripheral CD122HIGH AIMT cells (virtual memory) dominate in aged mice. Co-housing with feral mice changed the bacterial colonization of laboratory strains, but had only minimal effects on the CD8+ T-cell compartment including AIMT cells.

Signals for antigen-independent differentiation of memory CD8+ T cells

“…Whether T IM and T VM are different stages of one T AIM subset or different subsets is still the topic of ongoing discussion [ 4 , 16 , 36 ]. It has recently been proposed that CD122 expression can function as marker to distinguish T IM and T VM in the periphery, with T IM cells having lower expression of CD122 than T VM but higher than T N [ 11 ]. A detailed overview of T AIM surface markers is provided in Table 1 .…”

“…Expression of CD122 is induced by EOMES and T-bet [ 37 ]. Lower CD122 expression in T IM compared to T VM [ 11 ]. T IM and T VM [ 13 , 15 ] CD49d low α4β-Integrin; Part of the very late antigen-4 (VLA4) integrin that is involved in homing of effector T cells to the site of infection.…”

“…In aged mice, the percentage and absolute number of T AIM is again increased [ 9 , 11 , 28 , 71 ]. The precise mechanism that contributes to this increase is unknown, but also in older individuals T AIM cells depend on a combination of TCR and cytokine signaling.…”

“…Similar to T AIM in young mice, T AIM cells in aged mice still depend on IL-15, as was demonstrated by the absence of T VM in aged IL-15 KO mice [ 6 ]. Furthermore, expression of CD122, part of the IL-15 receptor, is increased on a subset of T AIM cells in aged BALB/c mice compared to young mice [ 11 ]. Taken together, this suggests that T AIM cells that accumulate in older animals require similar TCR and cytokine signals as early-developed T AIM cells.…”

“…This raises the question whether increased or decreased pathogen exposure affects T AIM differentiation. Several studies have shown that T AIM cells are also present in mice housed under germ-free conditions in a similar frequency as in SPF mice [ 11 – 13 ]. The presence of T AIM cells in ‘dirty’ feral mice has only recently been investigated.…”