Reviving the killers: all you need is IL-2

Comment on Moll et al, page 3081

Natural killer T (NKT) cells, which link innate to adaptive immunity, are targeted by HIV-1 and selectively lost in HIV-infected individuals. In this issue of Blood, Moll and colleagues report that IL-2 treatment of HIV patients effectively restores NKT cells.

Human invariant natural killer T (NKT) cells are a unique subset of T lymphocytes that are defined by the expression of a highly restricted T-cell receptor–(TCR) repertoire specific for glycolipid antigens and restricted by the CD1d molecule.¹  Although NKT cells represent a very small portion of lymphocytes (between 0.01% and 1% of peripheral blood mononuclear cells), they appear to respond more rapidly to triggering of their TCRs and display very potent effector functions, including cytotoxicity and robust secretion of cytokines such as IFNγ and IL-4.¹  Both their diverse cytokine profile and readiness to display their effector functions suggest that NKT cells may have important regulatory functions during immune responses. Indeed, it has been shown that NKT cells can regulate autoimmune diseases and facilitate responses to tumors as well as a wide range of infectious agents.¹ 

Recently, several groups reported that NKT cells that express CD4 and CCR5 are highly susceptible to HIV infection and are depleted in HIV-infected individuals.^2-4  Given the important role of NKT cells in potentially linking innate to adaptive immune responses, their loss in HIV-infected subjects may have several pathologic consequences, including impaired responses to opportunistic infections and tumors. Now, in this issue of Blood, Moll and colleagues show that it is possible to restore NKT cell numbers in HIV-infected individuals by administrating a combination of IL-2 and antiretroviral therapy.

Prior clinical trials have shown that IL-2 therapy is beneficial to HIV-infected patients in substantially expanding conventional CD4⁺ T cells, which can be further maintained by continued intermittent IL-2 administration.⁵  Antiretroviral treatment given in conjunction with IL-2 serves to suppress virus replication that may be induced by IL-2–mediated activation of T cells, thus maintaining low viral loads. More importantly, expanded cells in IL-2–treated patients are composed of both naive and memory T cells as well as Foxp3⁺ regulatory T cells.

In the current study, Moll et al show that IL-2 therapy not only increased overall NKT cell numbers but also resulted in expansion of both the CD4⁺ and CD4^– subsets of NKT cells. Furthermore, as an additional benefit, NKT cells expressing the HIV coreceptor CCR5 were decreased on the surface of both NKT cell subsets, which could contribute to protection of NKT cells from HIV infection and HIV-mediated cell death.

How IL-2 treatment expands NKT cells, whether this will be a sustained self-regeneration, and what impact upon preventing immune deficiency results from HIV-mediated destruction of T cells are some of the questions that remain to be answered. It is not known how NKT cells are replenished inhealthy adults, since it seems that very few precursors are present in the thymus. It is therefore conceivable that IL-2 either directly or indirectly stimulates the remaining peripheral NKT cells to expand. It will be important to determine if there are precursor NKT cells in the periphery and whether the turnover of these cells constantly replenishes the “effector” NKT cell pool, akin to conventional CD4⁺ effector T cells that are derived from naive precursors. ▪