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Expression of CD8? identifies a distinct subset of effector memory CD4 + T lymphocytes
Immunology, 2006
Circulating CD4 + CD8 + T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques. Two distinct populations of CD4 + CD8 + T cells were identified: the dominant one was CD4 hi CD8 lo and expressed the CD8aa homodimer, while the minor population was CD4 lo CD8 hi and expressed the CD8ab heterodimer. The majority of CD4 hi CD8a lo T cells exhibited an activated effector/memory phenotype (CCR5 lo CD7-CD28-HLA-DR +) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4 hi CD8a lo T cells compared to single-positive CD4 + T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4 hi CD8a lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4 hi CD8a lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4 + T cells expressing CD8a represent an effector/memory subset of CD4 + T cells and that this cell population can be depleted during the course of SIV infection.
Expression of CD8? identifies a distinct subset of effector memory CD4+T lymphocytes
Immunology, 2006
Circulating CD4 + CD8 + T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4 + CD8 + T cells in rhesus macaques. Two distinct populations of CD4 + CD8 + T cells were identified: the dominant one was CD4 hi CD8 lo and expressed the CD8aa homodimer, while the minor population was CD4 lo CD8 hi and expressed the CD8ab heterodimer. The majority of CD4 hi CD8a lo T cells exhibited an activated effector/memory phenotype (CCR5 lo CD7-CD28-HLA-DR +) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4 hi CD8a lo T cells compared to single-positive CD4 + T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4 hi CD8a lo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4 hi CD8a lo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4 + T cells expressing CD8a represent an effector/memory subset of CD4 + T cells and that this cell population can be depleted during the course of SIV infection.
Human CD8+ and CD4+ T Cell Memory to Lymphocytic Choriomeningitis Virus Infection
Journal of Virology, 2011
understood. Thus, we analyzed the breadths, magnitudes, and differentiation phenotypes of memory LCMVspecific CD8 ؉ and CD4 ؉ T cells in three human donors displaying a variety of disease outcomes after accidental needle stick injury or exposure to LCMV. Although only a small cohort of donors was analyzed at a single time point postinfection, several interesting observations were made. First, we were able to detect LCMV-specific CD8 ؉ and CD4 ؉ T cell responses directly ex vivo at 4 to 8 years after exposure, demonstrating the longevity of T cell memory in humans. Second, unlike in murine models of LCMV infection, we found that the breadths of memory CD8 ؉ and CD4 ؉ T cell responses were not significantly different from one another. Third, it seemed that the overall CD8 ؉ T cell response was augmented with increasing severity of disease, while the LCMV-specific CD4 ؉ T cell response magnitude was highly variable between the three different donors. Next, we found that LCMV-specific CD8 ؉ T cells in the three donors analyzed seemed to undergo an effector memory differentiation program distinct from that of CD4 ؉ T cells. Finally, the levels of expression of memory, costimulatory, and inhibitory receptors on CD8 ؉ and CD4 ؉ T cell subsets, in some instances, correlated with disease outcome. These data demonstrate for the first time LCMV-specific CD8 ؉ and CD4 ؉ T cells in infected humans and begin to provide new insights into memory T cell responses following an acute virus infection.
The Journal of Immunology, 2001
Infection of mice with a series of heterologous viruses causes a reduction of memory CD8 ؉ T cells specific to viruses from earlier infections, but the fate of the virus-specific memory CD4 ؉ T cell pool following multiple virus infections has been unknown. We have previously reported that the virus-specific CD4 ؉ Th precursor (Thp) frequency remains stable into long-term immunity following lymphocytic choriomeningitis virus (LCMV) infection. In this study, we questioned whether heterologous virus infections or injection with soluble protein CD4 Ags would impact this stable LCMV-specific CD4 ؉ Thp memory pool. Limiting dilution analyses for IL-2-producing cells and intracellular cytokine staining for IFN-␥ revealed that the LCMV-specific CD4 ؉ Thp frequency remains relatively stable following multiple heterologous virus infections or protein Ag immunizations, even under conditions that dramatically reduce the LCMV-specific CD8 ؉ CTL precursor frequency. These data indicate that the CD4 ؉ and CD8 ؉ memory T cell pools are regulated independently and that the loss in CD8 ؉ T cell memory following heterologous virus infections is not a consequence of a parallel loss in the memory CD4 ؉ T cell population.
The Journal of Immunology
Generally, it has been assumed that memory T cells are dormant and inactive cells in the absence of their specific Ag. Recent work has challenged this assumption by showing that a portion of the CD8+ memory T cell pool is in cycle. In this study, we demonstrate that a significant number of blast-size memory CD8+ T cells in mice, long after lymphocytic choriomeningitis virus (LCMV) infection, mediate cytolysis against highly sensitive targets without any in vivo or in vitro restimulation and expansion with Ag. Peptide-coated RMA-S targets were sufficiently sensitive to detect low but significant cytolytic activity in bulk 51Cr release assays in nonstimulated LCMV-specific splenic memory CTL populations. Most of the directly cytotoxic activity was against the GP33 epitope, and this persisted throughout the lifetime of the mouse following infection. The cytotoxic activity was not inhibited by cyclosporin A, indicating that these cells were already in an active state and not dependent o...
Four Functionally Distinct Populations of Human Effector-Memory CD8+ T Lymphocytes
The Journal of Immunology, 2007
In humans, the pathways of memory and effector T cell differentiation remain poorly defined. We have dissected the functional properties of ex vivo effector-memory (EM) CD45RA ؊ CCR7 ؊ T lymphocytes present within the circulating CD8 ؉ T cell pool of healthy individuals. Our studies show that EM T cells are heterogeneous and are subdivided based on differential CD27 and CD28 expression into four subsets. EM 1 (CD27 ؉ CD28 ؉ ) and EM 4 (CD27 ؊ CD28 ؉ ) T cells express low levels of effector mediators such as granzyme B and perforin and high levels of CD127/IL-7R␣. EM 1 cells also have a relatively short replicative history and display strong ex vivo telomerase activity. Therefore, these cells are closely related to central-memory (CD45RA ؊ CCR7 ؉ ) cells. In contrast, EM 2 (CD27 ؉ CD28 ؊ ) and EM 3 (CD27 ؊ CD28 ؊ ) cells express mediators characteristic of effector cells, whereby EM 3 cells display stronger ex vivo cytolytic activity and have experienced larger numbers of cell divisions, thus resembling differentiated effector (CD45RA ؉ CCR7 ؊ ) cells. These data indicate that progressive up-regulation of cytolytic activity and stepwise loss of CCR7, CD28, and CD27 both characterize CD8 ؉ T cell differentiation. Finally, memory CD8 ؉ T cells not only include centralmemory cells but also EM 1 cells, which differ in CCR7 expression and may therefore confer memory functions in lymphoid and peripheral tissues, respectively.