Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane–enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell–mediated cytotoxicity and specific ligand recognition by cell surface–activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell–activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell–activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.
Jacob Hanna, Tsufit Gonen-Gross, Jonathan Fitchett, Tony Rowe, Mark Daniels, Tal I. Arnon, Roi Gazit, Aviva Joseph, Karoline W. Schjetne, Alexander Steinle, Angel Porgador, Dror Mevorach, Debra Goldman-Wohl, Simcha Yagel, Michael J. LaBarre, Jane H. Buckner, Ofer Mandelboim
Submitter: Ofer Mandelboim | oferman@md2.huji.ac.il
The Hebrew University, Hadassah Medical School
Published February 3, 2005
We have recently provided compelling evidence that activated human NK cells can function as APCs and directly stimulate T cell responses 1. Furthermore, we demonstrated for the first time that NK cells acquire their APC-like phenotype after killing of target cells and that they are even able to prime naïve T cells proliferation 1.
Accumulating evidences provided by us and by others 1-5 further substantiated these novel observations. TAP-2 deficiency is an extremely rare disease and only very few cases of patients have been described so far 6-11. We specifically discuss the heterogeneity and differences in NK cell behavior among the various TAP-2 deficient patients. On the last page of the article by Markel et al. 11 we said:
“The TAP2-deficient patients present a major enigma to immunologists, as NK-mediated autoimmune manifestations are observed in some of these patients only during the third and fourth decades of life. It seems that the NK cells in these patients developed different mechanisms to overcome the NK-mediated autoimmunity. The acquisition of these mechanisms might be influenced by various factors such as exposure to different environmental pathogens. This could be the reason why, for example, the impaired expression of the NKp46 receptor was not observed in 2 other TAP2- deficient patients. Understanding of the molecular mechanisms responsible for the reduced NKp46 expression and the up-regulation of CEACAM1 might facilitate the development of novel therapy for these patients. Such treatments might also be useful in controlling NK cell killing activity in other medical situations such as bone marrow transplantations”.
Ofer Mandelboim, The Lautenberg Center for General and Tumor Immunology, The Hebrew University, Hadassah Medical School, Jerusalem, 91120, Israel
References
1. Hanna, J. et al. Novel APC-like properties of human NK cells directly regulate T cell activation. J Clin Invest 114, 1612-23 (2004).
2. Zingoni, A. et al. Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions. J Immunol 173, 3716-24 (2004).
3. Scala, G., Allavena, P., Ortaldo, J.R., Herberman, R.B. & Oppenheim, J.J. Subsets of human large granular lymphocytes (LGL) exhibit accessory cell functions. J Immunol 134, 3049-55 (1985).
4. Hanna, J. et al. Novel insights on human NK cells' immunological modalities revealed by gene expression profiling. J Immunol 173, 6547-63 (2004).
5. Hanna, J. et al. Proteomic analysis of human natural killer cells: insights on new potential NK immune functions. Mol Immunol 42, 425-31 (2005).
6. Moins-Teisserenc, H.T. et al. Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class-I molecules. Lancet 354, 1598-603 (1999).
7. Zimmer, J. et al. Activity and phenotype of natural killer cells in peptide transporter (TAP)-deficient patients (type I bare lymphocyte syndrome). J Exp Med 187, 117-22 (1998).
8. Zimmer, J. et al. Inefficient protection of human TAP-deficient fibroblasts from autologous NK cell-mediated lysis by cytokines inducing HLA class I expression. Eur J Immunol 29, 1286-91 (1999).
9. Vitale, M. et al. Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells. Blood 99, 1723-9 (2002).
10. Markel, G. et al. Biological function of the soluble CEACAM1 protein and implications in TAP2-deficient patients. Eur J Immunol 34, 2138-48 (2004).
11. Markel, G. et al. The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients. Blood 103, 1770-8 (2004).
Submitter: Jacques Zimmer | jacques.zimmer@crp-sante.healthnet.lu
Centre de Recherche Public de la Santé (CRP-Santé)
Published February 2, 2005
I read with interest the JCI paper by Hanna et al. [1] about the APC- like properties of NK cells and their expression of HLA class II and T cell costimulatory molecules. This work nicely shows that activated NK cells are capable of priming naïve CD4+ T lymphocytes and more generally participate in T cell stimulation. Interestingly, the results from a recent paper by Zingoni et al. [2] go in the same direction, as these authors show the expression of the T cell costimulatory molecules OX40L and CD86 on activated NK cells and their involvement in the triggering of proliferation and cytokine production of CD4+ T cells. Furthermore, Assarsson et al. [3] demonstrate that the NK cell receptor 2B4 (CD244) likewise contributes to NK – T cell interactions by mediating an activating effect on the proliferation of both CD4+ and CD8+ T lymphocytes.
All these studies thus strongly suggest that the regulation of adaptive immunity by NK cells is not only based on cytokine production, but also on direct interactions between NK cells and T cells mediated by several ligand – receptor pairs. In addition, they strengthen the concept of the immune system functioning as a network established between different cell types. In this context, NK – T cell interactions are yet another example besides the already well known bidirectional interactions between NK cells and dendritic cells [4-5].
Hanna et al. [1] also include in their study NK cells from TAP- deficient patients. Upon activation, these cells express T cell costimulatory molecules only weakly compared to normal NK cells and are inefficient in activating T lymphocytes.
The consequence of TAP-deficiency is a very low level of cell surface expression of HLA class I molecules. As NK cells predominantly kill target cells with low or absent expression of HLA class I molecules, NK cell- mediated autoimmunity might be expected in these patients and indeed seems to occur to some extent, as shown by my previous group and others [6-8]. Nevertheless, Hanna et al. [1] integrate their observation of a low expression of T cell costimulatory molecules by TAP-deficient NK cells into their hypothesis that in TAP-deficient individuals, NK cell-mediated autoimmune attack is avoided by (i) the upregulation of inhibitory receptors [1,9] and (ii) the downregulation of activating NK cell receptors, and among these in particular NCR (natural cytotoxicity receptors) [1,9], as well as of T cell-activating molecules [1].
Even if these characteristics indeed apply to NK cells from the TAP- deficient patients explored by this group [1,9], they might not be generalized and not be considered to hold true in all TAP-deficient patients described so far. The two patients we studied neither display an overexpression of inhibitory receptors of the KIR family [10], nor a downregulation of NKp46 or of other NCR [11]. On the contrary, most NK cells from our patients are NKp46bright, and the receptor (as well as other activating receptors) is fully functional [11]. The expression levels of NKp46 are very heterogeneous between individuals and may also vary between individual NK cells in a given donor [12]. Thus, the low level of expression of NKp46 on NK cells from the TAP-deficient patients described by Hanna et al. [1,9] might reflect genetic variations between individuals rather than an adaptation of NK cells to the low expression of HLA class I molecules in order to avoid autoimmunity. At the best, it would be one mechanism among others, because in our patients, NK cells are not cytotoxic before activation despite significant expression of NKp46.
In my opinion, the precise mechanisms allowing NK cells from TAP- deficient patients to be tolerant, at least to some extent and under certain conditions, to class I-deficient autologous cells have not yet been fully discovered. Several groups have added useful pieces to the puzzle, but this cannot be the entire story. For example, the low expression of NKp46 described by Hanna et al. [1,9] is not found in all the patients and thus cannot explain all the experimental results obtained.
Jacques Zimmer, MD, PhD Laboratoire d’Immunogénétique-Allergologie Centre de Recherche Public (CRP) de la Santé 84 Val Fleuri L-1526 Luxembourg
References
1)Hanna J., Gonen-Gross T., Fitchett J., Rowe T., Daniels M., Arnon T.I., Gazit R., Joseph A., Schjetne K.W., Steinle A., Porgador A., Mevorach D., Goldman-Wohl D., Yagel S., LaBarre M.J., Buckner J.H., Mandelboim O. Novel APC-like properties of human NK cells directly regulate T cell activation. J Clin Invest 2004, 114, 1612-1623.
2)Zingoni A., Sornasse T., Cocks B.G., Tanaka Y., Santoni A., Lanier L.L. Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions. J Immunol 2004, 173, 3716-3724.
3)Assarsson E., Kambayashi T., Schatzle J.D., Cramer S.O., von Bonin A., Jensen P.E., Ljunggren H.G., Chambers B.J. NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions. J Immunol 2004, 173, 174-180.
4)Cooper M.A., Fehniger T.A., Fuchs A., Colonna M., Caligiuri M.A. NK cell and DC interactions. Trends Immunol 2004, 25, 47-52.
5)Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2002, 2, 957-964.
6)Zimmer J, Donato L, Hanau D et al. Inefficient protection of human TAP- deficient fibroblasts from autologous NK cell-mediated lysis by cytokines inducing HLA class I expression. Eur J Immunol 1999, 29, 1286-1291.
7)Moins-Teisserenc HT, Gadola SD, Cella M et al. Association of a syndrome resembling Wegener's granulomatosis with low surface expression of HLA class I-molecules. Lancet 1999, 354, 1598-1603.
8)Gadola SD, Moins-Teisserenc HT, Trowsdale J et al. TAP deficiency syndrome. Clin Exp Immunol 2000, 121, 173-178.
9)Markel G, Mussafi H, Ling KL et al. The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients. Blood 2004, 103, 1770-1778.
10)Zimmer J, Donato L, Hanau D et al. Activity and phenotype of natural killer cells in peptide transporter (TAP)-deficient patients (type I bare lymphocyte syndrome). J Exp Med 1998, 187, 117-122.
11)Vitale M., Zimmer J., Castriconi R., Hanau D., Donato L., Bottino C., Moretta L., de la Salle H., Moretta A. Analysis of natural killer cells in TAP2-deficient patients : expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells. Blood 2002, 99, 1723-1729.
12)Moretta A., Bottino C., Vitale M., Pende D., Cantoni C., Mingari M.C., Biassoni R., Moretta L. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001, 19, 197-223.