Enrichment of Immediate-Early 1 (m123/pp89) Peptide-Specific CD8 T Cells in a Pulmonary CD62L^loMemory-Effector Cell Pool during Latent Murine Cytomegalovirus Infection of the Lungs

Abstract

. 74:7496-7507, 2000). It was proposed that these cells represent antiviral "standby" memory cells whose functional role might be to help prevent reactivation of latent virus. The pool of pulmonary CD8 T cells was composed of two subsets defined by the T-cell activation marker L-selectin (CD62L): a CD62Lhi subset of quiescent memory cells, and a CD62L lo subset of recently resensitized memory-effector cells. In this study, we have continued this line of investigation by quantitating CD8 T cells specific for the three currently published antigenic peptides of mCMV: peptide YPHFMPTNL processed from the immediate-early protein IE1 (pp89), and peptides YGPSLYRRF and AYAGLFTPL, derived from the early proteins m04 (gp34) and M84 (p65), respectively. IE1-specific CD8 T cells dominated in acute-phase pulmonary infiltrates and were selectively enriched in latently infected lungs. Notably, most IE1-specific CD8 T cells were found to belong to the CD62L lo subset representing memory-effector cells. This finding is in accordance with the interpretation that IE1-specific CD8 T cells are frequently resensitized during latent infection of the lungs and may thus be involved in the maintenance of mCMV latency.In human cytomegalovirus (hCMV) infection after bone marrow transplantation (BMT), recovery from CMV disease correlates with efficient reconstitution of CD8 T cells (50). Preemptive cytoimmunotherapy by adoptive transfer of hCMVspecific CD8 T-cell clones was found to be beneficial in that it reduced the incidence of CMV disease in BMT recipients (51, 56). Proof of principle for the protective effect of antiviral CD8 T cells was provided by the model of murine CMV (mCMV) infection of BALB/c mice subjected to hematoablative treatment. Early experiments performed in the absence of BMT documented an antiviral and protective function of adoptively transferred mCMV-specific CD8 T cells in the lungs as well as in other target organs of the disease (44, 46, 48; for a review, see reference 23). More recently, the course of mCMV infection was analyzed in the specific context of hematolymphopoietic reconstitution after either syngeneic BMT (18,38,39) or BMT performed across a single major histocompatibility complex (MHC) class I antigen disparity (1). Prevention of a disseminated and fulminant interstitial CMV pneumonia by the antiviral function of endogenously reconstituted CD8 T cells was inferred from the following observations: (i) CD8 T cells rather than CD4 T cells were recruited to infected lungs much more efficiently than to uninfected lungs (18); (ii) lung-infiltrating, blastoid CD62L lo CD8 T cells were not randomly distributed in lung tissue but were found to colocalize with infected lung cells in inflammatory foci, thereby secluding the infected cells from health tissue (18, 38); (iii) when isolated from the infiltrates, these activated CD8 T cells exerted ex vivo cytolytic activity against infected target cells (18) and secreted gamma interferon (IFN-␥) upon polyclonal triggering via CD3ε (38); (iv) the kinetics of infilt...

Properties of murine CD8+CD27- T cells

“…CMV-infected mice show a marked increase in the percentage of CMVspecific CD8 + T cells during the latent phase of infection (100 to 400 days after infection [44,45]) and we here showed that analogous to the human situation, these late CMV-specific CD8 + T cells at peripheral sites had a CD27 -phenotype. CD27 expression is down modulated after repetitive interactions with its ligand, CD70.…”

The (gradual) rise of memory inflation

“…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…”

Protein delivery by subviral particles of human cytomegalovirus

“…10,11 IFN-g-based ELISPOT analyses were carried out as detailed by others. 32 Values given represent the mean number of spots of triplicate wells and the standard deviation. (b) ELISPOT analysis of dendritic cells (DC), incubated with DB.…”