Infection History Determines the Differentiation State of Human CD8 ⁺ T Cells

Abstract

After the resolution of the acute phase of infection, otherwise quiescent antigen-experienced CD8؉ T cells confer rapid protection upon reinfection with viral pathogens or, in the case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8 ؉ T cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses to immediate effector functions for persistent viruses. We here show that both the differentiation stage, defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28, and CD27, and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8 ؉ T cells. Furthermore, virusspecific CD8؉ T cells targeting different respiratory syncytial virus-, influenza A virus-, Epstein-Barr virus (EBV)-, human cytomegalovirus (hCMV)-, and HIV-1-specific epitopes adopt distinct T-bet and Eomes expression patterns that appear to be installed early during the primary response. Importantly, the associations between surface phenotype, T-bet/Eomes expression levels, and the expression of markers that predict CD8؉ T-cell function change according to viral infection history, particularly against the background of HIV-1 and, to lesser extent, of human cytomegalovirus and/or Epstein-Barr virus infection. Thus, the functionality of human antigen-experienced CD8 ؉ T cells follows at least two dimensions, one outlined by the surface phenotype and another by the T-bet/Eomes expression levels, which are determined by previous or persistent viral challenges. IMPORTANCE Functional human CD8؉ T-cell subsets have been defined using surface markers like CD45RA, CCR7, CD28, and CD27. However, the induction of function-defining traits, like granzyme B expression, is controlled by transcription factors like T-bet and Eomes. Here, we describe how T-bet and Eomes levels distinctly relate to the expression of molecules predictive for CD8؉ T-cell function in a surface phenotype-independent manner. Importantly, we found that central memory and effector memory CD8 ؉ T-cell subsets differentially express T-bet, Eomes, and molecules predictive for function according to viral infection history, particularly so in the context of HIV-1 infection and, to lesser extent, of latent EBV-and/or hCMV-infected, otherwise healthy adults. Finally, we show that the distinct phenotypes and T-bet/Eomes levels of different virus-specific CD8 ؉ T-cell populations are imprinted early during the acute phase of primary infection in vivo. These findings broaden our understanding of CD8 ؉ Tcell differentiation. T he process of viral and host coevolvement has selected for antiviral CD8ϩ T-cell responses that are successful in ensuring survival of the host. As an apparent consequence, human circulating virus-specific CD8 ϩ T cells display distinct phenotypic and functional properties according to the virus or viral proteins they target (1-3). Acute viruses, such as respiratory syncytial vir...

The Transcription Factor Hobit Identifies Human Cytotoxic CD4+ T Cells

“…In contrast, the cytotoxic molecule granzyme K did not associate with Hobit (Figure 2D). This result is supported by previous reports showing that granzyme K, in contrast to Hobit, is not abundantly expressed in effector CD8 + T cells (20). To further investigate the characteristics of Hobit + T cells, we assessed the association of this transcription factor with key properties of cytotoxic T cells.…”

“…In contrast to the Hobit − fraction, the Hobit + CD4 + and CD8 + T cells lacked CCR7 expression (Figure 2F). These data suggest that Hobit + T cells do not respond to CCR7-dependent signals that instruct homing to lymphoid organs, in line with the observation that cytotoxic CD4 + and CD8 + T cells are absent from this compartment (20). …”

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

“…Infection history has recently been shown to alter the proportion of EOMES and TBX21 producing cells in blood [40] including infection with the near ubiquitous Epstein-Barr virus (EBV). Given that EBV is necessary for MS [41] and abnormalities in both NK and CD8 memory cells are known to be associated with MS and poor clearance of EBV, we investigated if the ETlow phenotype predicted poor control of EBV using anti-EBNA-1 IgG levels as a marker of EBV control.…”

Divide, Conquer, and Sense: CD8+CD28− T Cells in Perspective

“…An additional pool of non-recirculating tissue-resident memory cells (Trm) has also been described (14). Despite certain phenotypic and functional overlap among these CD8 + T cell pools, this classification has been most useful to describe the level of differentiation that the CD8 + T cell compartment has endured under different inflammatory settings, such as autoimmunity, cancer, and acute and chronic viral responses (15–17). Yet, perhaps the most significant achievement has been the identification of genes differently expressed by these pools, allowing to envision novel roles for CD8 + T cells (7, 18–20).…”

“…Nowadays, alterations in CD8 + CD28 − T cells have been reported in almost every chronic inflammatory disease. Studies performed on CMV-seropositive elderly showed that a sizable fraction of CD8 + CD28 − T cells contains CMV-specific CD8 + T cells (17). The description in the elderly of an association between the accumulation of CD8 + CD28 − T cells, a phenomenon called memory CD8 + T cell inflation (36), CMV seropositivity, a decrease in survival rate and faulty in vivo humoral and cellular responses to vaccination, brought about the view that CD8 + Tem cells were terminally differentiated dysfunctional cells that contributed to immunosenescence and susceptibility to develop chronic inflammatory diseases (35–40).…”