Abstract
Cytolytic CD4+ T cells play a prominent role in chronic viral infection. CD4+ CTLs clones specific for HIV-1 Nef and Gag are capable of killing HIV-1 infected CD4+ T cells and macrophages. Additionally, HIV-specific cytolytic CD4+ T cell responses in acute HIV infection are predictive of disease progression. CD57 expression on CD4s identifies cytolytic cells. These cells were dramatically increased in chronic HIV infection. CD57 expression correlated with cytolytic granules, granzyme B and perforin expression. They express lower CCR5 compared to CD57– cells, have less HIV total DNA, and were a minor component of the HIV reservoir. A small percentage of CD57+ CD4+ CTLs from EC were HIV-specific, could upregulate IFNγ with Gag peptide stimulation, express cytolytic granule markers and maintain TbethighEomes+ transcription factor phenotype. This was not observed in viraemic controllers. The maintenance of HIV-specific CD4 cytolytic function in Elite controllers together with CD8 CTLs may be important for the control of HIV viraemia and of potential relevance to cure strategies.
Highlights
Observations have been made since the late 1970s that CD4+ T cells are not merely helper cells, but can have cytolytic activity [1, 2]
This was confirmed by a study that observed in acute HIV infection that CD57+ CD4+ T cells were predominantly perforin+, granzyme B+ and Eomes+ [8], which suggests that CD57 expression may identify cytolytic CD4+ T cells
There was a median of 3.56% (IQR: 0.66–17.21%) within the CD4+ subset and ten-fold higher expression in the CD8+ subset [21.5% (13.03–59.64%)] (Figure 1A). To show that these CD57+ CD4+ T cells were potentially cytolytic, we stained for cytolytic granule markers Granzyme B and Perforin
Summary
Observations have been made since the late 1970s that CD4+ T cells are not merely helper cells, but can have cytolytic activity [1, 2]. CD4 CTLs were previously observed in HIV infection by Appay et al and were defined as antigen experienced, terminally differentiated with CD8 CTLs-like phenotype i.e., CD27−CD28−CD45RO+CCR7-perf+gzmA+, and that their killing mechanism was granzyme and perforin dependent [10, 11] This was confirmed by a study that observed in acute HIV infection that CD57+ CD4+ T cells were predominantly perforin+, granzyme B+ and Eomes+ [8], which suggests that CD57 expression may identify cytolytic CD4+ T cells. CD4+ CTLs clones specific for HIV Gag were generated from seronegative donors; these clones together with Nef-specific CD4+ CTLs clones were shown to be capable of killing HIV1 infected CD4+ T cells and macrophages [12] The presence of these HIV-specific cytolytic CD4+ T cell responses in acute HIV infection was highly predictive for disease outcome [13]. CD4 CTLs may potentially act in concert with CD8 CTLs to control HIV viraemia, and may be an important factor that distinguishes Elite and Viraemic control
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