Memory Inflation during Chronic Viral Infection Is Maintained by Continuous Production of Short-Lived, Functional T Cells

Abstract

Summary During persistent murine cytomegalovirus (MCMV) infection the T cell response is maintained at extremely high levels for the life of the host. These cells closely resemble human CMV-specific cells which comprise a major component of the peripheral T cell compartment in most people. Despite a phenotype that suggests extensive antigen-driven differentiation, MCMV-specific T cells remain functional and respond vigorously to viral challenge. We hypothesized that a low rate of antigen-driven proliferation would account for the maintenance of this population. Instead, we found that most of these cells divide only sporadically in chronically infected hosts and have a short half-life in circulation. The overall population is supported, at least in part, by memory cells primed early in infection as well as recruitment of naïve T cells at late times. These data show that memory inflation is maintained by a continuous replacement of short-lived, functional cells during chronic MCMV infection.

The (gradual) rise of memory inflation

“…The third feature observed was maintained effector functions such as cytokine release—in contrast to exhausted CD8 + T cells 8. There are certainly some differences in the level of cytokine production comparing inflationary populations and classical non‐inflationary memory cells in the same model, but over time there does not appear to be clear attrition of such functionality (and the lack of transcriptional and phenotypic markers of exhaustion is consistent with this) 3, 4, 16, 17. The findings were given some further relevance since they are quite parallel to those seen in human responses to HCMV—in other words very large responses identifiable by tetramer, with a phenotype described as “effector‐memory” (also CCR7, CD62L, CD28, CD27, CD127 low) and with maintained function.…”

“…Adoptive transfer experiments and other data suggest a half‐life of the cells of around 2 months 17, 67. Thus, although the actual fraction of cells proliferating on any 1 day is not high as caught in cross‐section (eg, via BrDU or Ki67 staining),3 there is nevertheless substantial turnover of the memory population.…”

“…First was the distinct phenotype of the tetramer‐positive populations. These emerged as having “effector‐memory” profiles as judged by the expression pattern of molecules such as CCR7, CD62L, CD28, CD27, and CD127 (all low) 3, 16, 17. This molecular pattern suggests homing to non‐lymphoid tissues and indeed the second feature is accumulation not only in blood and spleen where it was first noted but in many such tissues such as lung and liver, as opposed to lymph nodes 1, 3, 13.…”

“…Since the populations of inflationary cells are large, these lend themselves to analysis by flow cytometry and more recently gene expression studies, such that many groups have described their distinct phenotypic characteristics on the most abundant cells 17, 49. Some of these have been discussed already as they are embedded in the definition—an effector‐memory phenotype as defined by lack of expression of lymph node homing markers such as CCR7 and CD62L 3, 13.…”

“…However, other co‐inhibitory and co‐stimulatory receptor molecules are upregulated at the cell surface compared to conventional memory cells 61. These over‐expressed genes and molecules include Klrc1 (NKG2A), Klrg1 (KLRG1), Klre1 , Klra1 (Ly‐49c), and Klrk1 (NKG2D) 16, 17. The functions in vivo are not yet well explored but it might be they perform some similar “tuning” activity eg, in preventing overstimulation and promoting long‐term survival.…”