Progressive loss of T cell function is an important mechanism of chronic HIV-1-infection. PD-1 has been primarily used to describe exhausted T cells. Recently Tim-3 has been identified as additional marker for dysfunctional T cells. Tim-3 positive cells have not been defined in detail.
In this study we investigated the expression of PD-1 and TIM-3 on T cells from HIV-1-infected individuals.
We found that in the viremic patients only a small percentage of T cells expressed Tim-3 (mean: 4.1%). In contrast, a significant amount of T cells were PD-1 positive (mean 36.8%) and PD-1 was expressed at much higher levels than Tim-3. Nevertheless we found a trend to higher numbers of Tim-3 positive cells in viremic than in aviremic HIV-infected and even lower numbers in healthy individuals. When analysing CD8 T cells regarding CD45RA expression we found a striking difference between Tim-3 and PD-1 positive T cells: Tim-3 expressing cells were found in the CD45RA positive subset (p < 0.5) whereas PD-1 expression was nearly exclusively found on the CD45RA negative subset (p < 0.5). To further characterise the Tim-3 positive subset we performed multicolour staining using antibodies to various T cells markers including CD28 and CD57. Although CD57 expression and loss of the CD28 molecule are both associated with T cell senescence, Tim-3 expressing cells were exclusively found in the CD57 positive subset whereas is was not restricted to CD28 negative T cells.
In contrast to the PD-L/PD-1 pathway, blockingTim-3 did not enhance HIV-specific T cell proliferation or IFN g secretion.
Furthermore, whereas PD-1 positive cells have previously been shown to be increased in HIV-infected patients with discordant immune response, Tim-3 expression did not differ between patients with or without immune restoration on HAART.
Taken together our data implicate that Tim-3 defines a novel subset of terminally differentiated T cells.
- T cells