Evolution of diverse antiviral CD8⁺ T cell populations after murine cytomegalovirus infection

Abstract

Cytomegalovirus (CMV) is a major human pathogen normally controlled by cellular immune responses. The infection can be modeled in the mouse using murine CMV (MCMV). During the latent phase of infection, two different patterns of CD8 + T cell responses have been observed: some specificities show increasing frequencies over time ("memory inflation"), while others, which are present acutely, are barely detectable at later time points. This distinction is independent of initial immunodominance. We analyzed the extent to which such responses differ functionally and tracked both their population distribution and their evolution over time. We observed two clear patterns of memory development that diverged early after infection. Acutely, CD8 + T cells directed against all epitopes showed similar activation, phenotype and distribution. Thereafter, one set of responses ("inflationary") increased in frequency over time, was found in high numbers in non-lymphoid organs and was associated with an activated (CD28 low CD27 low CD122 low ) phenotype. In contrast, CD8 + T cells responses specific for other MCMV epitopes ("non-inflationary") showed a slow reversion to a classical "central" memory phenotype without enrichment in non-lymphoid organs. A simple model to describe the equilibrium state in MCMV is presented, which may point to previously unexplored antiviral populations present after human CMV 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.…”

“…At a similar time to this, Ann Hill's group performed some very detailed mapping experiments using vectors and peptide libraries to map the dominant CMV‐specific CD8 + T‐cell responses in the C57BL/6 mouse. Thus in different mouse strains, an “inflationary” and a classical response were seen to evolve in parallel against distinct peptide epitopes even within the same animal 3, 4…”

“…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. The third feature observed was maintained effector functions such as cytokine release—in contrast to exhausted CD8 + T cells 8.…”

“…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. It is certainly also the case that cells found in lymph nodes with these specificities retain expression of or re‐express such molecules, although these are a minority (in proportion) 50…”

“…It is a striking phenomenon that was made quite evident by the use of MHC‐peptide tetramers to track responses in the infected animals over time 2, 3, 4. The term is now in reasonably common use5, 6 and the actual features of the responses induced which can be called “inflationary” are quite robustly reproducible between different laboratories using different virus stocks, mouse lines, and infection protocols.…”