CD4+CD28null T lymphocytes resemble CD8+CD28null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients

Abstract

HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.

Lymph node and circulating T cell characteristics are strongly correlated in end-stage renal disease patients, but highly differentiated T cells reside within the circulation

“…In addition, CMV changed the T cell differentiation status in PB drastically, while no significant alterations were observed within LN with regard to T cell differentiation and ageing parameters. These late differentiated T cells then can respond to IL-15 produced by the inflamed parenchyma, proliferate and exert their cytotoxic function [46][47][48]. PB seems to harbour the majority of terminally differentiated T cells, while LNs do not harbour this specific subset of T cells.…”

“…Fractalkine is considered a major player in inflammatory responses, recruiting leucocytes into the inflamed tissue [43][44][45]. These late differentiated T cells then can respond to IL-15 produced by the inflamed parenchyma, proliferate and exert their cytotoxic function [46][47][48]. Whether the T cell characteristics in the LN might provide a better predictive model for clinical outcomes, such as the development of (co-stimulatory blockade-resistant) rejection and infection after, for example, kidney transplantation is subject to further investigation.…”

CD4+CD28null T cells are not alloreactive unless stimulated by interleukin-15

“…As alloreactive T cells reside within CD4 + CD28 null T cells, we set out to evaluate whether exogenous cytokines could induce the proliferation of alloreactive CD4 + CD28 null T cells. This investigation showed that IL‐15 and IL‐21, which are cytokines known to stimulate memory T cells, provided the highest fold‐increase of CD4 + CD28 null T cell frequency (Figure C). Based on these results, we continued to analyze the effect of the cytokines IL‐15 with and without IL‐21 at 10 ng/mL.…”

“…These mechanisms together suggest that these cells could be harmful for the renal allograft, if the optimal conditions are met. Whether these cells can be called exhausted is a matter of debate, because they are still able to proliferate and exert cytotoxic functions in multiple ways . Their function also seems to be stimulus dependent.…”

“…Allogeneic stimulation was performed with or without IL‐15 (10 ng/mL; Peprotech Inc., London, UK) and/or IL‐21 (10 ng/mL; Peprotech Inc.). The use of these cytokines was based on our experiments (see Results) and studies showing the effects of IL‐15 and IL‐21 on memory T cells . We chose 10 ng/mL because no differences were seen between stimulation with 10 or 50 ng/mL (data not shown).…”