Functional activity of natural killer cells and killer T cells in mice after ovarian transplantation

Tashkent Postgraduate Medical Institute, Ministry of Health of the USSR. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Lopatkin). Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 9, pp. 273–275, September, 1991.     

Alteration of T cells and natural killer cells during chickenpox in infancy

To determine the reasons for the low immune response and the mild morbidity of chickenpox in infancy, we investigated alteration of T cells and natural killer (NK) cells during chickenpox in children <1 year and 2 years old using flow cytometry. The CD4/CD8 ratio decreased only in the <1-year-old group from the acute to the convalescent phase (P<0.05). The CD3–CD16+CD56+ and CD57–CD16+ counts increased in the <1-year-old group, but those in the 2-year-old group did not increase from the acute to the convalescent phase. The CD3–CD16+CD56+ counts and the CD57-CD16+ counts and percentage were larger in the <1-year-old group than those in the 2-year-old group (P=0.001,P=0.002, andP<0.05) in the convalescent phase. These results seem to indicate that the low immune response in infancy after chickenpox are related to the small number of CD8 in contrast with CD4 and that increased subsets of NK cells during chickenpox may correlate to the mild morbidity of chickenpox in infancy.     

Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin‐like receptors

Deep characterization of the frequencies, phenotypes and functionalities of liver and peripheral blood natural killer (NK), natural killer T (NKT) and T cells from healthy individuals is an essential step to further interpret changes in liver diseases. These data indicate that CCR7, a chemokine essential for cell migration through lymphoid organs, is almost absent in liver NK and T cells. CD56^bright NK cells, which represent half of liver NK cells, showed lower expression of the inhibitory molecule NKG2A and an increased frequency of the activation marker NKp44. By contrast, a decrease of CD16 expression with a potential decreased capacity to perform antibody‐dependent cellular cytotoxicity was the main difference between liver and peripheral blood CD56^dim NK cells. Liver T cells with an effector memory or terminally differentiated phenotype showed an increased frequency of MAIT cells,T‐cell receptor‐γδ (TCR‐γδ) T cells and TCR‐αβ CD8⁺ cells, with few naive T cells. Most liver NK and T cells expressed the homing markers CD161 and CD244. Liver T cells revealed a unique expression pattern of killer cell immunoglobulin‐like receptors (KIR) receptors, with increased degranulation ability and higher secretion of interferon‐γ. Hence, the liver possesses a large amount of memory and terminally differentiated CD8⁺ cells with a unique expression pattern of KIR activating receptors that have a potent functional capacity as well as a reduced amount of CCR7, which are unable to migrate to regional lymph nodes. These results are consistent with previous studies showing that liver T (and also NK) cells likely remain and die in the liver.     

Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy

Regulatory T (Treg) cells and natural killer (NK) cells are key players in the immune system. The interaction between these two cell types has been reported to be beneficial in healthy conditions such as pregnancy. However, in the case of certain pathologies such as autoimmune diseases and cancer this interaction can become detrimental, as Treg cells have been described to suppress NK cells and in particular to impair NK cell effector functions. This review aims to discuss the recent information on the interaction between Treg cells and NK cells under healthy and pathologic conditions, to describe the specific conditions in which this interaction takes place, the effect of Treg cells on hematopoietic stem cell differentiation and the consequences of this interaction on the optimization of immunotherapeutic protocols.     

Adipose invariant natural killer T cells

Adipose tissue is a dynamic organ that makes up a substantial proportion of the body; in severe obesity it can account for 50% of body mass. Details of the unique immune system resident in human and murine adipose tissue are only recently emerging, and so it has remained a largely unexplored and unappreciated immune site until now. Adipose tissue harbours a unique collection of immune cells, which often display unusual functions compared with their counterparts elsewhere in the body. These resident immune cells are key to maintaining tissue and immune homeostasis, yet in obesity their chronic aberrant stimulation can contribute to the inflammation and pathogenesis associated with obesity. Anti‐inflammatory adipose‐resident lymphocytes are often depleted in obesity, whereas pro‐inflammatory immune cells accumulate, leading to an overall inflammatory state, which is a key step in the development of obesity‐induced metabolic disease. A good example is invariant natural killer T (iNKT) cells, which make up a large proportion of lymphocytes in human and murine adipose tissue. Here, they are unusually poised to produce anti‐inflammatory or regulatory cytokines, however in obesity, iNKT cells are greatly reduced. As iNKT cells are potent transactivaors of other immune cells, and can act as a bridge between innate and adaptive immunity, their loss in obesity represents the loss of a major regulatory population. Restoring iNKT cells, or activating them in obese mice leads to improved glucose handling, insulin sensitivity, and even weight loss, and hence represents an exciting therapeutic avenue to be explored for restoring homeostasis in obese adipose tissue.     

Carbohydrate specificity of the recognition of diverse glycolipids by natural killer T cells

Summary:  Most T lymphocytes recognize peptide antigens bound to or presented by molecules encoded in the major histocompatibility complex (MHC). The CD1 family of antigen-presenting molecules is related to the MHC-encoded molecules, but CD1 proteins present lipid antigens, mostly glycolipids. Here we review T-lymphocyte recognition of glycolipids, with particular emphasis on the subpopulation known as natural killer T (NKT) cells. NKT cells influence many immune responses, they have a T-cell antigen receptor (TCR) that is restricted in diversity, and they share properties with cells of the innate immune system. NKT cells recognize antigens presented by CD1d with hexose sugars in α-linkage to lipids, although other, related antigens are known. The hydrophobic alkyl chains are buried in the CD1d groove, with the carbohydrate exposed for TCR recognition, together with the surface of the CD1d molecule. Therefore, understanding the biochemical basis for antigen recognition by NKT cells requires an understanding of how the trimolecular complex of CD1d, glycolipid, and the TCR is formed, which is in part a problem of carbohydrate recognition by the TCR. Recent investigations from our laboratories as well as studies from other groups have provided important information on the structural basis for NKT-cell specificity.     

TCR Valpha14 natural killer T cells function as effector T cells in mice with collagen-induced arthritis

Natural killer (NK) T cells are a unique, recently identified cell population and are suggested to act as regulatory cells in autoimmune disorders. In the present study, designed to investigate the role of NKT cells in arthritis development, we attempted to induce arthritis by immunization of type II collagen (CIA) in Jalpha281 knock out (NKT-KO) and CD1d knock out (CD1d-KO) mice, which are depleted of NKT cells. From the results, the incidence of arthritis (40%) and the arthritis score (1.5 +/- 2.2 and 2.0 +/- 2.7) were reduced in NKT-KO and CD1d-KO mice compared to those in respective wild type mice (90%, 5.4 +/- 3.2 and 2.0 +/- 2.7, P < 0.01). Anti-CII antibody levels in the sera of NKT-KO and CD1d-KO mice were significantly decreased compared to the controls (OD values; 0.32 +/- 0.16 and 0.29 +/- 0.06 versus 0.58 +/- 0.08 and 0.38 +/- 0.08, P < 0.01). These results suggest that NKT cells play a role as effector T cells in CIA. Although the cell proliferative response and cytokine production in NKT-KO mice after the primary immunization were comparable to those in wild type mice, the ratios of both activated T or B cells were lower in NKT-KO mice than wild type mice after secondary immunization (T cells: 9.9 +/- 1.8% versus 16.0 +/- 3.4%, P < 0.01, B cells: 4.1 +/- 0.5% versus 5.1 +/- 0.7%, P < 0.05), suggesting that inv-NKT cells contribute to the pathogenicity in the development phase of arthritis. In addition, IL-4 and IL-1beta mRNA expression levels in the spleen during the arthritis development phase were lower in NKT-KO mice, while the IFN-gamma mRNA expression level was temporarily higher. These results suggest that inv-NKT cells influence cytokine production in arthritis development. In conclusion, inv-NKT cells may promote the generation of arthritis, especially during the development rather than the initiation phase.     

Perennial allergic rhinitis and chronic sinusitis: correlation with rhinologic risk factors

BACKGROUND: The reported association of allergy and sinusitis varies greatly between study, and the exact role of allergy in predisposing to sinusitis is not clear. We attempted to determine whether patients with perennial allergic rhinitis are at greater risk of developing sinusitis with respect to a control group, and to determine whether there is a correlation between rhinomanometry, endoscopy, and nasal swab, and computed tomography (CT) findings. METHODS: Forty adult patients with perennial allergic rhinitis underwent CT scans of the paranasal sinuses, and the results were then compared to CTs of the paranasal sinuses of 30 control subjects. All allergic patients underwent nasal endoscopy, nasal swab, and active anterior rhinomanometry, and the results were studied in relation to the CT findings. RESULTS: We found sinusitis in 67.5% of the allergic patients and in 33.4% of the controls, with a statistically significant difference between the two groups (P = 0.017). Twenty-three patients had a positive nasal swab; 22 showed increased nasal resistance on rhinomanometry, and 36 had positive endoscopy, but the association of CT findings with endoscopy, rhinomanometry, or nasal swab was not statistically significant (P = 0.583, P = 1.00, P = 0.506, respectively). CONCLUSIONS: Allergic rhinitis is often associated with sinusitis, but the underlying mechanism has yet to be determined. Evidently, factors other than classical pathogen growth and mechanical factors, such as the association of the various factors and immunologic mechanisms, may contribute to the pathogenesis of chronic sinusitis in allergic patients.     

Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia

Recent advances in chronic lymphocytic leukaemia (CLL) treatment, more particularly through upfront use of anti-CD20 monoclonal antibodies, have prolonged patient progression-free survival. Nonetheless, apart from allogeneic stem cell transplantation, no curative treatment is available. One possible explanation for the lack of cure in CLL could be a defective immune anti-tumour response. As the result of abnormal HLA class I molecule expression, CLL cells escape from specific T-lymphocyte immunity but should be the target for the innate natural killer (NK) cell-mediated immune response. Defective NK cytotoxicity as the result of decreased expression of the natural cytotoxicity receptors (NCRs) NKp30/NCR3, NKp44/NCR2 and NKp46/NCR1 has been described in haematological malignancies such as acute myeloid leukaemia. This prompted us to focus our attention on NCR expression on NK cells from patients with CLL. Although we failed to detect any difference between CLL patients and healthy age-matched controls, a precise analysis of clinical data showed a correlation between decreased NCR expression and poor prognosis factors such as low haemoglobin level, high (>30×10(9) per litre) lymphocyte count or elevated C-reactive protein. Together, these observations support the rationale for restoration of normal NK cell functions in patients with CLL, putatively through the use of immune therapy protocols that already have demonstrated some benefit in acute myeloid leukaemia such as interleukin-2 plus histamine dihydrochloride.     

9.1C3分子对人NK细胞和T细胞细胞毒作用的抑制效应

目的探讨9.1C3分子是否作为抑制型受体调节NK细胞和T细胞的杀伤功能。方法用抗CD56抗体和羊抗鼠IgG免疫磁珠分离混合淋巴细胞培养中活化的淋巴细胞 ,分选CD56 细胞和CD56 -细胞分别作为效应细胞。采用重导向杀伤实验(redirectedkillingassay,RKA)观察抗9.1C3抗体对效应细胞杀伤小鼠肥大细胞瘤细胞P815作用的影响。结果发现人NK细胞和T细胞对P815细胞均有一定的杀伤作用 ,在效靶比为4∶1 ,2∶1和1∶1时 ,NK细胞和T细胞的杀伤率分别为:6.4% ,3.4% ,1.1%和21.2 % ,16.7 % ,6.5 %。用抗CD16和抗CD3抗体分别刺激NK细胞和T细胞时 ,它们对P815细胞的细胞毒作用显著增强 ;在相同的效靶比例 ,它们对P815的杀伤率分别为:47.1 % ,32.2% ,19.1 %和64.4 % ,50.3% ,39.5 %。但用抗9.1C3抗体刺激效应细胞时 ,不仅NK细胞的杀伤作用完全被抑制 ,CD16介导的NK细胞的杀伤作用也被明显下调 ,其杀伤率仅为18.5 % ,9.7 %和7.0 % ;但对CD3介导的T细胞的杀伤作用只轻度被抑制。结论9.1C3分子可能是一种新的抑制型杀伤细胞受体 ,对NK细胞和T细胞细胞毒作用的负调节可能有所不同。     

Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma

Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d^−/− mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d^−/− mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d^−/− mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model.     

Invariant natural killer T cells balance B cell immunity

Invariant natural killer T (iNKT) cells mediate rapid immune responses which bridge the gap between innate and adaptive responses to pathogens while also providing key regulation to maintain immune homeostasis. Both types of important iNKT immune responses are mediated through interactions with innate and adaptive B cells. As such, iNKT cells sit at the decision‐making fulcrum between regulating inflammatory or autoreactive B cells and supporting protective or regulatory B cell populations. iNKT cells interpret the signals in their environment to set the tone for subsequent adaptive responses, with outcomes ranging from getting licensed to maintain homeostasis as an iNKT regulatory cell (iNKT_reg) or being activated to become an iNKT follicular helper (iNKT_FH) cell supporting pathogen‐specific effector B cells. Here we review iNKT and B cell cooperation across the spectrum of immune outcomes, including during allergy and autoimmune disease, tumor surveillance and immunotherapy, or pathogen defense and vaccine responses. Because of their key role as influencers, iNKT cells provide a valuable target for therapeutic interventions. Understanding the nature of the interactions between iNKT and B cells will enable the development of clinical interventions to strategically target regulatory iNKT and B cell populations or inflammatory ones, depending on the circumstance.     

Probiotic antigens stimulate hepatic natural killer T cells

Increasing evidence suggests that gut flora play an important role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). Our previous studies show that hepatic natural killer T (NKT) cells play a significant role in the pathogenesis of NAFLD. In this study, we explore the mechanism by which modification of gut flora leads to the alteration of hepatic NKT cells and improvement of steatosis. Mice were fed a high‐fat (HF) diet to induce NAFLD. Some of them also received different doses of mixed‐strain probiotics (VSL#3); single‐strain probiotic (Bifidobacterium infantis) or antibiotics. Animal weight, glucose tolerance, liver steatosis and hepatic NKT cells were assessed. Lipid extracts from probiotics were tested for their ability to activate NKT cells. Toll‐like receptor 4 (TLR4) knockout mice were also evaluated for their responses to HF diet. High‐dose VSL#3 was more effective than low‐dose VSL#3 and B. infantis for the improvement of hepatic NKT cell depletion and steatosis. The lipids extracted from VSL#3 stimulated NKT cells both in vivo and in vitro. In contrast, lipids from B. infantis decreased α‐GalCer‐mediated NKT cell activation in vitro, but were able to stimulate NKT cells. TLR4 knockout mice have a similar response to HF‐diet‐induced NKT cell depletion and obesity. These results suggest that alterations in the gut flora have profound effects on hepatic NKT cells and steatosis, which are both strain‐specific and dose‐dependent, but not through TLR4 signalling. Furthermore, these data suggest that probiotics may contain bacterial glycolipid antigens that directly modulate the effector functions of hepatic NKT cells.     

Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection

Emerging evidence indicates that natural killer (NK) cells may contribute to liver injury in patients with hepatitis B virus (HBV) infection. Because HBV infection progresses through various disease phases, the cytolytic profiles of peripheral and intrahepatic NK cells in HBV‐infected patients remain to be defined. In this study, we comprehensively characterized intrahepatic and peripheral NK cells in a cohort of HBV‐infected individuals, and investigated their impact on liver pathogenesis during chronic HBV infection. The study population included 34 immune‐clearance (IC) patients, 36 immune‐tolerant (IT) carriers and 10 healthy subjects. We found that the activity of peripheral NK cells from IC patients was functionally elevated compared to IT carriers and controls, and NK cell activation was indicated by an increased expression of CD69, CD107a, interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α. Further analysis showed that the increased activity of both peripheral and hepatic NK cells was correlated positively with liver injury, which was assessed by serum alanine aminotransferase levels (ALT) and the liver histological activity index (HAI). Interestingly, the frequency of peripheral NK cells was reduced in IC patients (especially those with higher HAI scores of 3–4), but there was a concomitant increase in hepatic NK cells. The functionally activated NK cells are enriched preferentially in the livers of IC patients and skew towards cytolytic activity that accelerates liver injury in chronic hepatitis B (CHB) patients.     

Human natural killer (NK) cells present staphylococcal enterotoxin B (SEB) to T lymphocytes

Superantigen-mediated T cell activation requires the participation of antigen-presenting cells (APC). Once superantigen has bound class II MHC molecules on the surface of APC, it then can interact with the T cell receptor to induce T cell activation. Superantigen-mediated T lymphocyte activation, along with its consequent cytokine production is thought to be the basis for the pathophysiology of conditions such as toxic shock syndrome, Kawasaki''s disease and possibly rheumatoid arthritis. We examined the role of CD56⁺ NK lymphocytes in the interaction between superantigens and T lymphocytes. First, we found that a subpopulation of CD56⁺ cells freshly isolated from human peripheral blood expressed class II MHC molecules. The amount of HLA-DR expression varied between individuals, ranging from 9.3% to 37.7%. CD56⁺ (NK) cells were purified from the peripheral blood by cell sorting and were tested for their ability to support SEB-mediated T cell activation as assessed by surface expression of IL-2 receptor α-chain (CD25) on CD3⁺ lymphocytes. We observed that when enriched T cells were incubated with SEB in the presence of NK cells, there was a significant up-regulation of CD25 expression on the T cells. When HLA-DR⁺ cells were removed from sorted CD56⁺ populations, the remaining HLA-DR⁻ NK cells were unable to support SEB-mediated T cell activation. Also, SEB up-regulated the expression of HLA-DR on CD56⁺ cells in peripheral blood mononuclear cell (PBMC) populations after 24 h of incubation, implying that the ability of NK cells to function as superantigen-presenting cells is up-regulated by superantigens themselves. Together, these data demonstrate for the first time that human CD56⁺HLA-DR⁺ NK cells can function as superantigen-presenting cells, and imply that NK cells may be involved in the activation of non-specific T cell reactivity during early host defences against superantigen-elaborating microorganisms in vivo. Furthermore, the physical linkage of NK cells and T cells by the interaction of superantigen with HLA class II molecules and T cell receptors, respectively, may lead to NK cell activation and augmented lytic potential, helping to clear the body of superantigen-elaborating microorganisms.