Identification of the CD16low CD56low CD38pos Natural Killer Cell as a Key Subset in Patients with Multiple Myeloma

Background: Natural killer (NK) cells are classified as innate immune cells which can directly recognize and kill tumor cells without antigen sensitization. NK cell-based adoptive immunotherapy for blood malignancies has attracted more attention in recent years. Objective: To analyze different NK cell subsets in the peripheral blood and bone marrow (BM) of patients with multiple myeloma (MM). Methods: Using flow cytometry we analyzed: (i) the distribution of distinct NK cell subpopulations (i.e. CD16low CD56low, CD16pos CD56high, CD16neg CD56high, CD16high CD56low, CD16neg CD56low, CD16low CD56low CD38pos) in the BM from MM patients at distinct disease stages. (ii) the expression of NKG2D, DNAM-1 and NKp30, and (iii) the expression of CD107a in CD16low CD56low CD38pos and CD16low CD56low CD38neg NK cells subsets. Results: CD16low CD56low CD38pos was the dominant subset in BM from patients with MM at the CR stage with a decreased expression of NKp30. CD16low CD56low CD38pos subset showed a higher proportion of CD107a expression compared to CD16low CD56low CD38neg cells. In vitro experiments indicated that the CD16low CD56low CD38pos NK cell subset possesses more cytotoxicity than CD16low CD56low CD38neg NK cells. Conclusion: Our data suggest that CD16low CD56low CD38pos NK cells may reflect as an effector population with the potential therapeutic target in patients with MM. This group of cells may be useful for adoptive immunotherapy in MM in the future.     

Low perforin and elevated SHIP-1 expression is associated with functional anergy of natural killer cells in chronic HIV-1 infection

Natural killer (NK) cells are critical for the first-line defense in infection. Treated viremic HIV-1 infection is associated with the expansion of an anergic subset of CD3-CD56-CD16+ NK cells unable to respond to stimulation with MHC-devoid target cells or with mitogens. These CD3-CD56-CD16+ NK cells expressed SHIP-1 and had significantly reduced perforin levels. This observation suggests a mechanism for the reduced functional activity of CD3-CD56-CD16+ NK cells in chronic HIV-1 infection.     

Presence of distinct subsets of cytolytic CD8+ T cells in chronic HIV infection

Cytolytic T lymphocytes (CTL) play an important role in the control of HIV infection. The eventual failure to contain HIV-1 infection may arise because of a functional impairment of HIV-specific CTL. We evaluated Gag-specific cytotoxicity in HIV-1-positive Ugandans. Expression of CD107, a marker for cytolytic activity, was present in CD45RA(bright) and CD45RA(dim) CD8(+) T cell populations in HIV-infected individuals. The frequency of Gag-specific CD107(+)CD45RA(bright)CD28(-)CCR7(-) CD8(+) T cells decreased with CD4 cell depletion and correlated with the presence of Gag-specific T helper response. In contrast, the frequency of Gag-specific CD107(+)CD45RA(dim)CD28(-)CCR7(-) CD8(+) T cells within the same individuals has no significant association with viral load or CD4 cell count. The ratio of CD45RA(bright) to CD45RA(dim) CTL correlates significantly with CD4 cell count. This positive association decreases with antiretroviral treatment (ARV), indicating that suppression of viral replication alters the balance of circulating Gag-specific CD8(+) effector T cells. Subsets of cytolytic T cells may have distinct antiviral functions and further characterization of these effector CD8(+) T cells may yield important information on T cell regulation and dysfunction in HIV infection.     

Expansion of defective NK cells in early HIV type 1C infection: a consequence of reduced CD161 expression

Human immunodeficiency virus (HIV)-1 infection compromises the natural killer (NK) cell function and leads to defective control on virus multiplication. One of the major features of HIV-1 infection is the expansion of a functionally compromised defective NK cell subset (CD56(-)CD16(+)). We analyzed the NK cell subsets in early HIV infection to determine the effect of NK cell perturbation on the viral load set point, a marker of disease progression. We report that the defective NK cells are expanded in early HIV infection within 6-8 months of acquiring infection and are correlated with a higher plasma viral load set point, suggesting its utility as a predictive marker for disease progression. The expression of CD161, a molecular marker responsible for proliferation and differentiation of NK cells, was significantly down-regulated in the defective NK cells as compared to slow progressors (p=0.0009) and healthy controls (p=0.0003) and was correlated with a higher viral load set point in early HIV-1 infection (r=-0.6154, p=0.03), suggesting the probable role of CD161 expression in the impaired proliferation and differentiation of defective NK cells into the functional NK cells in early HIV infection. The reduction in CD161 expression on the defective NK cells in early HIV infection is thus indicative of the role of innate immune cells in early control of HIV infection.     

CD16- CD56+ natural killer cells after bone marrow transplantation.

Natural killer (NK) cells are phenotypically defined as lymphocytes expressing the antigens CD56 and mostly CD16 (Fc gamma RIII), but lacking CD3. A small CD3- CD16- CD56+ NK cell subset has been described in normal individuals representing less than 2% of peripheral blood lymphocytes. We analyzed here 70 patients for their reconstitution of the immune system during follow-up after autologous or allogeneic bone marrow transplantation. In 35% of these patients, two different NK cell subsets, namely CD56+dim and CD56+bright cells, were observed. The mean duration of these two subsets after transplant was 4 months. Sixty-five percent of the patients exhibited an increased number of NK cells, but only the typical CD16+ CD56+dim population. The CD56+bright subpopulation represented a particular CD3- CD16- NK subset, with posttransplant frequencies up to 70% of all NK cells and 40% of peripheral blood lymphocytes, respectively. In contrast to normal CD56+dim NK cells, CD56+bright cells coexpressed the activation antigens p75 beta-chain of interleukin-2 receptor (IL-2R), CD2R, and CD26, but were negative for CD16. NK and antibody-dependent cellular cytotoxicity activity of CD56+bright cells was low compared with CD56+dim NK cells. But using IL-2 and interferon gamma, their cytotoxicity could be enhanced even more than in CD56+dim lymphocytes. These different subsets may reflect distinct activation or differentiation steps of NK cells during reconstitution of the immune system. Their differential response to IL-2 may be of functional importance for posttransplant cytokine therapy.     

Revisiting human natural killer cell subset function revealed cytolytic CD56(dim)CD16+ NK cells as rapid producers of abundant IFN-gamma on activation

The two major functions of human natural killer (NK) cells are conventionally associated with distinct cell subsets. Thus, cytolytic activity is mostly confined to the CD56(dim)CD16(+) subset, whereas cytokine production is generally assigned to CD56(bright)CD16(+/-) cells. In this study, we reevaluated the functional capabilities of these NK subsets with regard to the production of IFN-γ at different time points after cell triggering via NKp46 and NKp30 activating receptors. Different from previous studies, cytokine production was also assessed at early intervals. We show that CD56(dim) NK cells produce IFN-γ already at 2 to 4 h, whereas no cytokine production is detected beyond 16 h. In contrast, CD56(bright) cells release IFN-γ only at late time intervals (>16 h after stimulation). The rapid IFN-γ production by CD56(dim) NK cells is in line with the presence of IFN-γ mRNA in freshly isolated cells. Rapid IFN-γ production was also induced by combinations of IL-2, IL-12, and IL-15. Our data indicate that not only cytolytic activity but also early IFN-γ production is a functional property of CD56(dim) NK cells. Thus, this subset can assure a rapid and comprehensive NK cell intervention during the early phases of innate responses.     

Analysis of natural killer (NK) cell activity and adhesion molecules on NK cells from umbilical cord blood

The activity of natural killer (NK) cells in human umbilical cord blood (CB) has been reported to be low, compared with that in adult peripheral blood (PB) in vitro. To examine the cause of this, after dividing the CD56+/CD3- cells in CB and PB into CD56bright and CD56dim NK cells, the NK cell activities and the expression of various surface antigens were assayed for each fraction. The NK cell activity of CD56dim NK cells in CB was significantly lower than that in PB (P = 0.0003), whereas, there was no significant difference between the NK cell activity of CD56bright NK cells in PB and CB. The expression levels of adhesion molecules (CD2, CD11a, CD18, DNAX accessory molecule-1), CD16, and CD57 for CD56dim NK cells in CB were significantly lower than those in PB, and approximately one-third of CB CD56dim NK cells were capable of forming conjugates with K562 cells, compared with PB CD56dim NK cells. Furthermore, the inhibition of both the NK cell activities and binding of CD56dim NK cells in PB and CB by monoclonal antibody against each of these adhesion molecules suggests that they play an important role in NK cell activity. These findings show that the low NK cell activity in CB is caused by the low NK cell activity of CD56dim NK cells and that the low expression level of adhesion molecules on CB CD56dim NK cells may contribute to this low NK cell activity.     

Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals

Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(-)/CD16(+) (CD56(-)) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56(-) NK fraction compared with that of CD56(+) NK cells was associated with extremely poor in vitro cytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56(-), as compared with the CD56(+) NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56(-) NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population.     

Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection

During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56(dim)CD16(+) NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94-NKG2C receptor and CD57 in CMV(+) donors. These CD57(+)NKG2C(hi) NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57(+)NKG2C(hi) NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57(+)NKG2C(hi) NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C(+) NK cells proliferated, became NKG2C(hi), and finally acquired CD57. Thus, we propose that CD57 might provide a marker of "memory" NK cells that have been expanded in response to infection.     

Immune reconstitution of CD56(dim) NK cells in individuals with primary HIV-1 infection treated with interleukin-2

Natural killer (NK) cells are believed to play a role in human immunodeficiency virus type 1 (HIV-1) disease progression, and NK cell levels are reduced in individuals with chronic HIV-1 infection. Interleukin (IL)-2 therapy results in an expansion of CD4(+) T cells as well as NK cells; however, little is known about the detailed effects of IL-2 therapy on NK cells in HIV-1 infection in general and in early infection in particular. Here, we investigated the effects of combined IL-2 therapy and antiretroviral therapy (ART) on the number, frequency, phenotype, and interferon (IFN)-gamma production of NK cells in individuals with early HIV-1 infection. Patients randomized to receive combined ART and IL-2 therapy predominantly expanded CD56(dim) NK cells, and the expansion was greater than in patients randomized to receive ART alone. Importantly, NK cell receptor expression and IFN-gamma production were maintained over time. This reconstitution of NK cells may be useful in helping contain viremia if patients discontinue therapy or develop drug resistance.     

CD16+ NK cells decrease in all stages of HIV infection through a selective depletion of the CD16+CD8+CD3- subset

Natural killer (NK) cell-related phenotypes were analyzed in human immunodeficiency virus (HIV) infection. Our study involved 168 HIV-infected patients (72 CDC Stage II, 48 Stage III, and 46 Stage IV) and 60 healthy individuals. Analyses were conducted using flow cytometry and monoclonal antibodies. In comparison to the control group, all patient groups showed a significant decrease (p less than 0.001) of the CD16+ and CD16+CD3- phenotypes; furthermore, the comparison among patient groups showed no significant difference. It seems, therefore, that the decrease begins in the asymptomatic stage (CDC II) and remains constant during the infection. CD16+ NK cells were further divided into two subsets: CD16+CD8+ and CD16+CD8-. This subdivision shows a severe selective depletion of the CD16+CD8+ subset, but not in the CD16+CD8- subset. The depletion of the CD16+CD8+ subset also appears in the CDC asymptomatic stage and remains constant in CDC stages III and IV. Elsewhere, we observed that CD16+CD8+ lymphocytes are CD3-; complementary analysis of CD3-CD8+ cells showed a depletion comparable to that of the CD16+CD8+ phenotype. Depletion of the CD3-CD8+ subset, which belongs to the NK cell compartment, was observed although the total CD8 population showed a statistically significant increase. We conclude that, in HIV infection, there is a quantitative decrease of the NK CD16+ cell population, which appears to be due to a selective depletion of the CD16+CD8+CD3- compartment. This severe depletion appears to begin early in the infection.     

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection induces elevated levels of inflammatory cytokines, which are mainly produced by the innate response to the virus. The role of NK cells, which are potent producers of IFN-γ and cytotoxicity, has not been sufficiently studied in the setting of SARS-CoV-2 infection. We confirmed a different distribution of NK cell subsets in hospitalized COVID-19 patients despite their NK cell deficiency. The impairment of this innate defense is mainly focused on the cytotoxic capacity of the CD56^dim NK cells. On the one hand, we found an expansion of the CD56^dimCD16^neg NK subset, lower cytotoxic capacities, and high frequencies of inhibitory 2DL1 and 2DL1/S1 KIR receptors in COVID-19 patients. On the other hand, the depletion of CD56^dimCD16^dim/bright NK cell subsets, high cytotoxic capacities, and high frequencies of inhibitory 2DL1 KIR receptors were found in COVID-19 patients. In contrast, no differences in the distribution of CD56^bright NK cell subsets were found in this study. These alterations in the distribution and phenotype of NK cells might enhance the impairment of this crucial innate line of defense during COVID-19 infection.     

Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation

In this study, we have characterized reconstitution of the natural killer (NK) cell repertoire after haploidentical CD34(+) selected hematopoietic stem cell transplantation (HSCT) for high-risk hematologic malignancies. Analysis focused on alloreactive single-KIR(+) NK cells, which reportedly are potent antileukemic effectors. One month after HSCT, CD56(bright)/CD56(dim) NK-cell subsets showed inverted ratio and phenotypic features. CD25 and CD117 down-regulation on CD56(bright), and NKG2A and CD62L up-regulation on CD56(dim), suggest sequential CD56(bright)-to-CD56(dim) NK-cell maturation in vivo. Consistently, the functional potential of these maturation intermediates against leukemic blasts was impaired. Mature receptor repertoire reconstitution took at least 3 months. Importantly, at this time point, supposedly alloreactive, single-KIR(+) NK cells were not yet fully functional. Frequency of these cells was highly variable, independently from predicted NK alloreactivity, and below 1% of NK cells in 3 of 6 alloreactive patients studied. In line with these observations, no clinical benefit of predicted NK alloreactivity was observed in the total cohort of 56 patients. Our findings unravel the kinetics, and limits, of NK-cell differentiation from purified haploidentical hematopoietic stem cells in vivo, and suggest that NK-cell antileukemic potential could be best exploited by infusion of mature single-KIR(+) NK cells selected from an alloreactive donor.     

Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset

During the innate immune response to infection, monocyte-derived cytokines (monokines), stimulate natural killer (NK) cells to produce immunoregulatory cytokines that are important to the host's early defense. Human NK cell subsets can be distinguished by CD56 surface density expression (ie, CD56(bright) and CD56(dim)). In this report, it is shown that CD56(bright) NK cells produce significantly greater levels of interferon-gamma, tumor necrosis factor-beta, granulocyte macrophage-colony-stimulating factor, IL-10, and IL-13 protein in response to monokine stimulation than do CD56(dim) NK cells, which produce negligible amounts of these cytokines. Further, qualitative differences in CD56(bright) NK-derived cytokines are shown to be dependent on the specific monokines present. For example, the monokine IL-15 appears to be required for type 2 cytokine production by CD56(bright) NK cells. It is proposed that human CD56(bright) NK cells have a unique functional role in the innate immune response as the primary source of NK cell-derived immunoregulatory cytokines, regulated in part by differential monokine production.     

Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation

Monocyte cytokines (ie, monokines) induce natural killer (NK) cells to produce interferon-gamma (IFN-gamma), which is critical for monocyte clearance of infectious pathogens and tumor surveillance. Human CD56bright NK cells produce far more IFN-gamma in response to monokines than do CD56dim NK cells. The kinases and phosphatases involved in regulating IFN-gamma production by monokine-activated NK cells are not clearly identified. SHIP1 is a 5' inositol phosphatase that dephosphorylates the phosphatidylinositol-3 kinase (PI-3K) product PI3,4,5P3. Here, we show that constitutive expression of SHIP1 is distinctly lower in CD56bright NK cells compared with CD56dim NK cells, suggesting it could be an important negative regulator of IFN-gamma production in monokine-activated NK cells. Indeed, overexpression of SHIP1 in CD56bright NK cells followed by monokine activation substantially lowered IFN-gamma production. This effect was not seen when NK cells were infected with a SHIP1 mutant containing an inactive catalytic domain. Finally, NK cells in SHIP1-/- mice produced more IFN-gamma in response to monokines in vivo than did NK cells from wild-type mice. Collectively, these results demonstrate that SHIP1 negatively regulates monokine-induced NK cell IFN-gamma production in vitro and in vivo and provide the first molecular explanation for an important functional distinction observed between CD56bright and CD56dim human NK subsets.     

Evolution of innate and adaptive effector cell functions during acute HIV-1 infection

Early events during acute human immunodeficiency virus type 1 (HIV-1) infection are critical in determining the course of disease progression. Cells of the innate and adaptive immune responses are involved in this acute response to infection; however, little is known about the coevolution of innate and adaptive effector cell populations during the initial phase of HIV-1 infection. Here, we have characterized the development of innate natural killer (NK) cell and adaptive HIV-1-specific CD8(+) T cell function during acute HIV-1 infection. Although NK cell populations were significantly expanded during acute infection before HIV-1 seroconversion, HIV-1-specific CD8(+) T cell responses were absent or weak and were inversely correlated with the level of NK cell activity. NK cell activity was directly correlated with the level of viral replication during acute HIV-1 infection and declined rapidly in subjects who initiated highly active antiretroviral therapy, whereas NK cell activity remained elevated in subjects who did not initiate therapy. Yet, reexposure to HIV-1 antigen during treatment discontinuation in chronic infection resulted in a synchronous increase in NK and CD8(+) T cell activity. Overall, these data demonstrate that expansion of the NK cell population precedes the development of adaptive HIV-1-specific CD8(+) T cells during acute infection but that both effector cell subsets respond with similar kinetics during chronic HIV-1 infection.     

Soluble HLA-G dampens CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD56bright and CD56dim NK cells

Soluble HLA-G (sHLA-G) inhibits natural killer (NK) cell functions. Here, we investigated sHLA-G-mediated modulation of (1) chemokine receptor and NK receptor expression and function and (2) cytokine and chemokine secretion in CD56bright and CD56dim NK cells. sHLA-G-treated or untreated peripheral blood (PB) and tonsil NK cells were analyzed for chemokine receptor and NK receptor expression by flow cytometry. sHLA-G down-modulated (1) CXCR3 on PB and tonsil CD56bright and CD56dim, (2) CCR2 on PB and tonsil CD56bright, (3) CX3CR1 on PB CD56dim, (4) CXCR5 on tonsil CD56dim, and (5) CD94/NKG2A on PB and tonsil CD56brigh) and CD56dim NK cells. Such sHLA-G-mediated down-modulations were reverted by adding anti-HLA-G or anti-ILT2 mAbs. sHLA-G inhibited chemotaxis of (1) PB NK cells toward CXCL10, CXCL11, and CX3CL1 and (2) PB CD56bright NK cells toward CCL2 and CXCL10. IFN-γ secretion induced by NKp46 engagement was inhibited by NKG2A engagement in untreated but not in sHLA-G-treated NK cells. sHLA-G up-regulated secretion of (1) CCL22 in CD56bright and CD56dim and (2) CCL2, CCL8, and CXCL2-CXCL3 in CD56dim PB NK cells. Signal transduction experiments showed sHLA-G-mediated down-modulation of Stat5 phosphorylation in PB NK cells. In conclusion, our data delineated novel mechanisms of sHLA-G-mediated inhibition of NK-cell functions.     

Diminished absolute counts of CD56dim and CD56bright natural killer cells in peripheral blood from Egyptian patients with hepatocellular carcinoma

Natural killer cells (NK) as components of the innate immunity substantially contribute to anti-tumor immune responses, NK cell subpopulations can be defined on the basis of the relative expression of CD16 and CD56 markers. Earlier research demonstrated a dramatic reduction in the frequency of peripheral blood CD56dimCD16+ NK subsets in hepatocellular carcinoma (HCC) patients compared with healthy subjects. We aim to assess the relative and absolute counts of natural killer cells subsets in hepatitis C-related HCC among Egyptian patients. Flowcytometric analysis of peripheral blood NK subsets was performed for HCV with HCC patients (n=20) and HCV without HCC patients (n=14) as compared to healthy control subjects (n=152). We found that HCC patients displayed a marked reduction in the relative frequency of peripheral CD56im subsets compared with healthy subjects. Moreover, there was a significant reduction in the absolute counts of CD56dim16+, CD56dim16- and CD56bright. In conclusion, this study demonstrated that the absolute counts of dim and bright NK cell subsets were decreased in different proportions in patients with HCV-related HCC that refers to a possible role for these cells, particularly CD 56 bright cells, in the immune response to HCC. This might aid in developing new therapeutic strategies targeting both NK subsets for HCC.     

肝癌患者外周血自然杀伤细胞的功能分析

目的 探讨肝癌患者外周血自然杀伤 (NK) 细胞的数目和功能,以进一步了解肝癌的发病机制. 方法 入选35例肝癌患者和24名健康人,用流式细胞仪检测外周血NK细胞亚群频率;通过检测NK细胞分泌干扰素(IFN) γ的能力和杀伤K562细胞的能力,评价NK细胞的功能.数据用均数±标准差(χ±s)表示,不同组间的比较采用SPSS13.0进行Mann-Whitney非参数检验分析.结果 与健康对照组相比,肝癌患者外周血NK细胞的频率明显降低 (12.19%±10.85%与24.01%±8.78%,u=4.01,P<0.01);其中CD56~(bright)CD16~(neg) NK细胞频率增加 (0.62%±0.39%与0.48%±0.28%,u=1.96,P<0.05),而CD56~(dim)CD16~(pos).NK细胞频率明显降低(11.59%±7.49%与22.66%±8.84%,u=3.92,P<0.01).肝癌患者外周血NK细胞经过佛波酯刺激后分泌IFN γ的能力降低 (有效细胞13.31%),并且对K562细胞的杀伤活性明显降低,以30:1、10:1、1:1与K562细胞混合后,其杀伤效率在肝癌组与对照组分别为16.72%±7.33%与26.29%±12.36%(u=2.52,P<0.05)、8.01%±4.40%与13.09%±5.03%(u=3.32,P<0.05)、3.51%±2.82%与3.42%±1.64%(u=1.56,P>0.05).结论 肝癌患者体内NK细胞功能受损,抗肿瘤能力下降,这可能是肝癌患者抗肿瘤免疫应答缺陷的机制之一.     

NK cytotoxicity against CD4+ T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand

HIV infection leads to a state of chronic immune activation and progressive deterioration in immune function, manifested most recognizably by the progressive depletion of CD4⁺ T cells. A substantial percentage of natural killer (NK) cells from patients with HIV infection are activated and express the natural cytotoxicity receptor (NCR) NKp44. Here we show that a cellular ligand for NKp44 (NKp44L) is expressed during HIV-1 infection and is correlated with both the progression of CD4⁺ T cell depletion and the increase of viral load. CD4⁺ T cells expressing this ligand are highly sensitive to the NK lysis activity mediated by NKp44⁺ NK cells. The expression of NKp44L is induced by the linear motif NH2-SWSNKS-COOH of the HIV-1 envelope gp41 protein. This highly conserved motif appears critical to the sharp increase in NK lysis of CD4⁺ T cells from HIV-infected patients. These studies strongly suggest that induction of NKp44L plays a key role in the lysis of CD4⁺ T cells by activated NK cells in HIV infection and consequently provide a framework for considering how HIV-1 may use NK cell immune surveillance to trigger CD4⁺ T cells. Understanding this mechanism may help to develop future therapeutic strategies and vaccines against HIV-1 infection.