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The Journal of Immunology, 2004, 172: 4667-4671.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: The Ontogeny and Function of Va14Ja18 Natural T Lymphocytes Require Signal Processing by Protein Kinase C{theta} and NF-{kappa}B1

Aleksandar K. Stanic, Jelena S. Bezbradica, Jang-June Park, Luc Van Kaer, Mark R. Boothby and Sebastian Joyce2

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The rapid and robust immunoregulatory cytokine response of Va14Ja18 natural T (iNKT) cells to glycolipid Ags determines their diverse functions. Unlike conventional T cells, iNKT lymphocyte ontogeny absolutely requires NF-{kappa}B signaling. However, the precise role of NF-{kappa}B in iNKT cell function and the identity of upstream signals that activate NF-{kappa}B in this T cell subset remain unknown. Using mice in which iNKT cell ontogeny has been rescued despite inhibition of NF-{kappa}B signaling, we demonstrate that iNKT cell function requires NF-{kappa}B in a lymphocyte-intrinsic manner. Furthermore, the ontogeny of functional iNKT cells requires signaling through protein kinase C{theta}, which is dispensable for conventional T lymphocyte development. The unique requirement of protein kinase C{theta} implies that signals emanating from the TCR activate NF-{kappa}B during iNKT cell development and function. Thus, we conclude that NF-{kappa}B signaling plays a crucial role at distinct levels of iNKT cell biology.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The immunoregulatory natural T (iNKT)3 cells express an invariant Va14Ja18 TCR {alpha}-chain predominantly paired with the Vb8.2 TCR {beta}-chain. They recognize lipid Ags such as the potent antitumor agent {alpha}-galactosylceramide ({alpha}GalCer) presented by CD1d. In vivo iNKT cell activation results in a rapid and robust secretion of both Th1- and Th2-type cytokines. These cytokines trans-activate other immune components, and hence iNKT cell response in vivo impacts both the innate and adaptive immune systems (reviewed in Ref. 1).

Because instructional processes largely determine the effector properties of lymphocytes during their development, we reasoned that unique molecular controls regulate the development of functional iNKT cells. Consistent with this prediction, we (2) and others (3, 4) reported recently that iNKT cells, in striking contrast to conventional T lymphocytes, require finely tuned NF-{kappa}B signaling for the early steps of iNKT cell development. The requirement for NF-{kappa}B1, a classical NF-{kappa}B subunit, in iNKT cell ontogeny is cell intrinsic (4), whereas the requirement for RelB, another NF-{kappa}B subunit, is cell extrinsic (3, 4). Furthermore, we found that NF-{kappa}B regulates iNKT cell ontogeny by suppressing apoptosis (2) and not proliferation (4), a conclusion supported by the fact that T lineage-specific Bcl-xL expression in NF-{kappa}B-deficient thymocytes completely rescues iNKT cell development and differentiation (2). These findings raise two important questions regarding iNKT cell ontogeny: 1) does NF-{kappa}B control iNKT cell function, and 2) which upstream signaling molecule(s) activate NF-{kappa}B in iNKT cells? In this study, we present evidence that the ontogeny of functional iNKT cells requires signals emanating from the TCR, which are relayed through protein kinase C (PKC){theta} and processed by NF-{kappa}B.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

C57BL/6 and B6.129-NF-{kappa}B10/0 (NF-{kappa}B10/0) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). B6.129-CD1d10/0 (5), B6-{Delta}Ntg, and C-{Delta}Ntg (6) mice have been described; B6.129-PKC{theta}0/0 (7) strain was a generous gift from D. Littman (Howard Hughes Medical Institute, New York University, New York, NY). C-{Delta}Ntg mice were bred to C-Lck-Bcl-xLtg mice, which constitutively express Bcl-xL in T lineage cells (8). All mice were bred and maintained in compliance with Vanderbilt University’s Institutional Animal Care and Use Committee regulations.

Abs and reagents

Abs and reagents for ELISA, and cell surface and intracellular staining were purchased from BD PharMingen (San Diego, CA) (for details, see Ref. 2), unless stated otherwise. {alpha}GalCer was generously provided by Kirin Brewery Company (Gunma, Japan). Preparation of CD1d1-{alpha}GalCer (CD1) tetramer, and its specificity and use have been described (9).

iNKT hybridoma stimulation

The N37-1H5a iNKT hybridoma was maintained as described (10). Approximately 5 x 104 hybridoma cells per well were mixed with 5 x 105 stimulator thymocytes and cocultured in triplicate for 18–20 h at 37°C. IL-2 secreted upon activation of the hybridoma was monitored by ELISA (9).

Measurement of cytokine responses

Each mouse was injected i.p. with 10 µg of {alpha}GalCer diluted in PBS from a 200 µg/ml stock solution in vehicle (0.05% v/v polysorbate-20 and 0.9% w/v NaCl) or vehicle. Four hours later, sera were collected, and IL-2, IL-4, and IFN-{gamma} were measured by ELISA (9).

In vitro iNKT cell activation

C57BL/6 splenocytes were dispersed by collagenase D (Roche Diagnostic, Somerville, NJ) treatment, washed, reacted with anti-CD11c-coated magnetic beads (Miltenyi Biotec, Auburn, CA) and separated using auto-MACS sorter (Miltenyi Biotec). Sorted DC were pulsed with {alpha}GalCer (1 µg/ml) for 6 h. Splenocytes from mice indicated in the figure were reacted with anti-MHC class II coated magnetic beads (Miltenyi Biotec), and the unbound T cell-enriched fraction was purified. After extensive washes with PBS, 1 x 105 {alpha}GalCer-pulsed DC were cocultured with 1 x 106 T cells for 8–9 h in the presence of 10 µg/ml brefeldin A (Sigma-Aldrich, St. Louis, MO) to block cytokine secretion and 3 µM monensin (Sigma-Aldrich) to prevent TCR internalization. T-enriched cells were also stimulated with 30 ng/ml PMA (Sigma-Aldrich) and 1 µM ionomycin (Sigma-Aldrich) for 8–9 h. Following stimulation, cells were blocked with anti-CD16/CD32 and stained with anti-CD3{epsilon}-PerCP-Cy5.5 and allophycocyanin-conjugated CD1 tetramer for 1.5 h at 4°C. After washing out excess reagents, cells were fixed and permeabilized with Cytofix/Cytoperm (BD PharMingen) and stained with anti-IFN-{gamma}-PE (XMG1.2).

Flow cytometry

Thymocytes and splenocytes of individual, littermate or age-matched (6–10 wk of age) mice were stained for four- and six-color flow-cytometric analyses with Abs and reagents as indicated in the figures. Four- and six-color flow cytometry were performed with FACSCalibur (BD Biosciences, San Diego, CA) and LSR-II (BD Biosciences), respectively, as described (2). Data were analyzed with FlowJo software (Tree Star, Ashland, OR). iNKT cell magnetic sorting and phenotypic analysis was performed as described (2).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
CD1d1 expression and Ag presentation remain unaltered in NF-{kappa}B-deficient mice

We (2) and others (4) demonstrated recently that inhibition of NF-{kappa}B signaling either by T cell-specific I{kappa}B{alpha}{Delta}Ntg ({Delta}Ntg), a dominant-negative form of I{kappa}B{alpha}, or targeted disruption of NF-{kappa}B1 severely perturbs iNKT cell development. In principle, this phenotype could be due to impaired CD1d1 expression or function. Therefore, we measured CD1d1 expression level and functional status on C57BL/6, NF-{kappa}B10/0, and {Delta}Ntg CD4+8+ double-positive thymocytes. The data revealed that CD1d1 expression is maintained independent of NF-{kappa}B signaling. Furthermore, {Delta}Ntg thymocytes are recognized by iNKT cell hybridomas, excluding a role for NF-{kappa}B in the expression of natural iNKT cell Ag (data not shown).

NF-{kappa}B controls iNKT cell function

Although single-subunit deficiency of NF-{kappa}B in NF-{kappa}B10/0 mice impairs iNKT cell ontogeny (2, 4), ~30% of wild-type cell numbers are detected in the spleen (2). It is possible that the remaining NF-{kappa}B10/0 iNKT cells could respond to Ag by signaling through other NF-{kappa}B subunits (e.g., RelA and cRel). Therefore, we measured the in vivo cytokine response in C57BL/6 and NF-{kappa}B10/0 mice using supraoptimal dose of the glycolipid Ag {alpha}GalCer to drive cytokine production (11). NF-{kappa}B10/0 mice produced very little, if any, IL-2, IL-4, or IFN-{gamma} in response to {alpha}GalCer compared with wild-type iNKT cells (Fig. 1A).



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  		FIGURE 1. NF-{kappa}B is essential for iNKT cell function. A, C57BL/6, B6.129-NF-{kappa}B10/0, and B6.129-CD1d10/0 mice were administered 10 µg of {alpha}GalCer or vehicle i.p. Four hours later, serum IL-2, IL-4, or IFN-{gamma} was determined by ELISA. B, BALB/C, C-{Delta}Ntg, C-{Delta}Ntg;Bcl-xLtg, and C.129-CD1d10/0 iNKT cell function was determined as described above. C, MHC class II-positive leukocyte-depleted C57BL/6, B6.129-NF-{kappa}B10/0, and B6.129-PKC{theta}0/0 splenocytes were stimulated in vitro for 8–9 h with either {alpha}GalCer-pulsed CD11c+ DC magnetically purified from C57BL/6 splenocytes or PMA and ionomycin in the presence of brefeldin A (BFA) to block cytokine secretion and monensin to prevent TCR internalization. Intracellular IFN-{gamma} in iNKT and T cells were detected following electronic gating (top row) of CD3{epsilon}+CD1 tetramer+ cells (middle three rows) and CD3{epsilon}+CD1 tetramer− cells (bottom row), respectively. Numbers within plots indicate percentage of total T cells expressing intracellular IFN-{gamma}. D, In vitro activation of BALB/c, C-{Delta}Ntg, and C-{Delta}Ntg;Bcl-xLtg iNKT and T cells was monitored as in C; also see panel for description. Data are representative of three similar experiments.

 
The reduced numbers of NF-{kappa}B10/0 iNKT cells and the need for low-level tonic stimulation of dendritic cells (DC) to adequately up-regulate costimulatory molecules, may have caused poor in vivo iNKT cell activation by {alpha}GalCer. Therefore, MHC class II-positive leukocyte-depleted splenocytes, which are T cell-enriched, were stimulated in vitro for 8–9 h with CD11c+ DC magnetically purified from C57BL/6 splenocytes and pulsed with {alpha}GalCer. As a control, T cell-enriched splenocytes were stimulated with PMA and ionomycin to bypass TCR-based signals. Intracellular IFN-{gamma} within activated iNKT cells and conventional T lymphocytes was monitored. As expected from the in vivo functional studies, {alpha}GalCer does not activate NF-{kappa}B10/0 iNKT cells in vitro, whereas PMA and ionomycin did (Fig. 1C). Thus, NF-{kappa}B1, in addition to its role in development, controls iNKT cell response to Ag in vivo.

Although the few remaining NF-{kappa}B10/0 iNKT cells appear dysfunctional, and CD1d1 in NF-{kappa}B10/0 mice adequately presents the self Ag (data not shown), NF-{kappa}B signals may control other properties of APCs that regulate iNKT cell activation. NF-{kappa}B signaling in C-{Delta}Ntg mice is impaired only within the T cell lineage, and we have previously shown that Bcl-xL fully rescues iNKT cell numbers in NF-{kappa}B signaling-deficient mice (2). Therefore, C-{Delta}Ntg;Bcl-xLtg mice represent an excellent model to study the cell-intrinsic role of NF-{kappa}B in iNKT cell function. We administered {alpha}GalCer to BALB/c, C-{Delta}Ntg, C-{Delta}Ntg;Bcl-xLtg, and C.129-CD1d10/0 mice and measured IL-2, IL-4, and IFN-{gamma} levels 4 h later. The results revealed that, despite the rescue of iNKT cells to normal numbers in C-{Delta}Ntg;Bcl-xLtg mice, in vivo cytokine response to {alpha}GalCer remained negligible (Fig. 1B). Similarly, {alpha}GalCer did not activate C-{Delta}Ntg and C-{Delta}Ntg;Bcl-xLtg iNKT cells in vitro (Fig. 1D). Thus, NF-{kappa}B signaling to a downstream target(s) other than Bcl-xL is required for mature iNKT cell function.

Ontogeny of functional iNKT cells requires PKC{theta}

Because TCR-induced NF-{kappa}B signaling in mature conventional T lymphocytes is controlled by PKC{theta} (7, 12, 13), we hypothesized that induction of NF-{kappa}B during iNKT cell activation in response to Ag in vivo is mediated by PKC{theta}. To test this hypothesis, we first determined whether iNKT cells develop in PKC{theta}0/0 mice. PKC{theta}0/0 thymus and spleen contain less than one-third the number of iNKT cells compared with PKC{theta}+/0 thymus and spleen (Fig. 2, A and B). Phenotypic analysis of PKC{theta}0/0 thymic iNKT cells revealed the presence of previously defined (14) immature (DX5−NK1.1− and DX5+NK1.1−) and mature (DX5+NK1.1+ and DX5−NK1.1+) cells, but their ratio was skewed, in that there were more immature PKC{theta}0/0 iNKT cells (Fig. 2C). Furthermore, phenotypic analysis using iNKT cell differentiation markers (CD69, CD44, Ly49C/I, CD122, Bcl-2, Ki67, Cyclin D1) confirmed that, despite their reduced numbers, ~50% of the remaining mature PKC{theta}0/0 iNKT cells appear to resemble wild-type mature iNKT cells (Fig. 2C).



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  		FIGURE 2. PKC{theta} is essential for the development of functional iNKT cells. A, Prevalence of thymic and splenic iNKT cells in B6.129-PKC{theta}+/0 and B6.129-PKC{theta}0/0 mice were determined as follows. Leukocytes were reacted with CD1 tetramer-allophycocyanin, anti-CD8{alpha}-FITC (thymus), anti-B220-FITC (spleen), and anti-CD3{epsilon}-PerCP-Cy5.5 Abs and examined by flow cytometry. Contour plots reveal iNKT cells (CD1 tetramer+CD3{epsilon}+) within electronically gated CD8LO thymic and B220LO splenic lymphocytes. Numbers within plots indicate percentage of iNKT cells among total lymphocytes. B, Absolute numbers of iNKT cells in B6.129-PKC{theta}+/0 (n = 5) and B6.129-PKC{theta}0/0 (n = 5) mice were calculated from total splenocyte number and percentages of each population. C, Phenotype of iNKT cells in B6.129-PKC{theta}+/0 and B6.129-PKC{theta}0/0 thymi magnetically depleted of CD8high cells was determined by six-color flow cytometry. At least one million events were collected. iNKT cells were identified as CD1 tetramer+ and CD3{epsilon}-PerCP-Cy5.5+ cells. Their phenotype was investigated with anti-NK1.1-PE-Cy7, anti-DX5-PE, anti-CD69-FITC, anti-CD44-PE, anti-Ly49C/I-FITC, and anti-CD122-PE. Intracellular Bcl-2 levels were evaluated by intracellular staining with anti-Bcl-2-PE. Intracellular Cyclin D1 and Ki67 levels were evaluated by staining with anti-Cyclin D1-FITC, anti-Ki67-PE, and IgG2a-isotype control-FITC. D, The functional status of CD1d1 expressed by B6.129-PKC{theta}+/0 and B6.129-PKC{theta}0/0 thymocytes was determined by their ability to activate N37–1H5a, a Va14Ja18 iNKT hybridoma in a stimulator-responder coculture system. Secreted IL-2, an indicator of iNKT cell activation by wild-type and mutant thymocytes, was monitored by ELISA. E, B6.129-PKC{theta}+/0 and B6.129-PKC{theta}0/0 mice were administered 10 µg of {alpha}GalCer or vehicle i.p. Four hours later, serum cytokine levels were determined by ELISA as in Fig. 1A. Data are representative of three similar experiments.

 
iNKT cell development in PKC{theta}0/0 mice may be disrupted due to impaired CD1d1 expression or Ag presentation in the thymus. However, we found that, akin to PKC{theta}+/0 thymocytes, those from PKC{theta}0/0 mice present iNKT cell Ag to iNKT hybridomas (Fig. 2D). Despite expression of functional CD1d1 molecules, PKC{theta}0/0 mice do not respond to {alpha}GalCer in vivo (Fig. 2E) or in vitro (Fig. 1C). Thus, unlike conventional T cells, which do not require PKC{theta} for their development and maturation, both the ontogeny and function of iNKT cells require PKC{theta}.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In summary, the function of iNKT cells critically depends on NF-{kappa}B signaling in a manner distinct from Bcl-xL induction. Furthermore, the ontogeny of functional iNKT cells depends on signals emanating from PKC{theta}, which is known to be tightly linked to TCR signaling. Together, these findings establish a novel role for NF-{kappa}B in lymphocyte development and function.

Recent findings from several laboratories (3, 4) including ours (2) have indicated that the ontogeny of iNKT cells is critically dependent upon intact NF-{kappa}B signaling in a lineage-specific manner, because conventional T lymphocyte ontogeny proceeds relatively normally (6, 15). Because NF-{kappa}B1 deficiency accounts for only a part of the {Delta}Ntg phenotype, other members of the NF-{kappa}B family must also be involved in iNKT cell ontogeny. Because the effects of RelB are cell extrinsic, and NF-{kappa}B2 deficiency only mildly impairs iNKT cell ontogeny (3, 4), RelA signaling may have a partial, nonredundant role in iNKT cell development. These findings notwithstanding, NF-{kappa}B1-deficient iNKT cells do not respond to in vivo stimulation with {alpha}GalCer, and produce only small amounts of IFN-{gamma} upon in vitro stimulation. Thus, the ontogeny of functional iNKT cells requires signal processing by NF-{kappa}B1. Furthermore, the role of NF-{kappa}B1 in signaling iNKT cell ontogeny and function is unique to this lymphocyte lineage, because NF-{kappa}B1 deficiency only mildly, if at all, affects conventional T cell biology (16).

If the only role of NF-{kappa}B in iNKT cell ontogeny is to suppress apoptosis, it would be predicted that C-{Delta}Ntg;Bcl-xLtg mice, which have a normal complement of iNKT cells (2), would rapidly and robustly respond to administered glycolipid Ag. However, {alpha}GalCer did not activate C-{Delta}Ntg;Bcl-xLtg iNKT cells in vivo or in vitro. In conventional CD4+ {Delta}Ntg T lymphocytes, in vitro and in vivo TCR stimulation in conjunction with costimulation elicit IL-2 and IL-4 responses (17, 18). Hence, the functional deficiency of NF-{kappa}B signaling-deficient iNKT cells is less likely due to defective IL-2 and IL-4 gene regulation. Thus, NF-{kappa}B signaling is critical for both the ontogeny and function of iNKT cells.

TCR engagement activates PKC isoforms, which relay signals to downstream effectors. PKC{theta} plays a critical role in mature, conventional T cell activation, but does not affect {beta}-selection or positive and negative selection (7, 13). In striking contrast, we found that PKC{theta} deficiency severely impairs thymic iNKT cell ontogeny, suggesting the coupling of Va14Ja18 iNKT cell receptor engagement to NF-{kappa}B signaling in the thymus. Thymic iNKT cell deficiency in PKC{theta}0/0 mice is less severe compared with {Delta}Ntg mice but similar to that found in NF-{kappa}B10/0 mice, suggesting a partially redundant role with another PKC isoform, possibly PKC{epsilon}, because PKC{epsilon} appears to play a critical role in conventional T cell ontogeny (19). These findings imply unique signaling events in the ontogeny of functional iNKT cells. Furthermore, the critical requirement for PKC{theta} in iNKT cell ontogeny suggests unique organization of the Va14Ja18 TCR and proximal signaling apparatus essential to the development of this T lymphocyte lineage. This conclusion is consistent with our recent results from biochemical studies of glycolipid Ag-TCR interactions (11).

Under certain circumstances, activation of iNKT cells is pathogenic (20, 21, 22, 23, 24). The preferential requirement for NF-{kappa}B signaling in iNKT cell ontogeny and function may explain why Th2 responses evolve in {Delta}Ntg mice, but fail to induce airway hyperreactivity (17). Thus, our findings suggest that short-term therapeutic inhibition of NF-{kappa}B signaling has substantial clinical potential.


   Acknowledgments
 
We thank Kirin Brewery for synthetic {alpha}GalCer, D. R. Littman for B6-129-PKC{theta}0/0 mice, K. Hayakawa for iNKT hybridomas, W. Khan for PMA and ionomycin, A. J. Joyce for technical assistance, M. H. McReynolds for {Delta}Ntg mouse genotyping, and W. Briley and M. Henderson for secretarial assistance.


   Footnotes
 
1 This work was supported by National Institutes of Health (HL68744, AI50953, NS44044, HL61752, AI49460, and AI42284), Juvenile Diabetes Research Foundation, Human Frontiers in Science Program, and Sandler Family Foundation grants. Back

2 Address correspondence and reprint requests to Dr. Sebastian Joyce, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, A4223 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232. E-mail address: sebastian.joyce{at}vanderbilt.edu Back

3 Abbreviations used in this paper: iNKT, invariant natural T; {alpha}GalCer, {alpha}-galactosylceramide; PKC, protein kinase C; DC, dendritic cell. Back

Received for publication September 8, 2003. Accepted for publication February 13, 2004.


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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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M. Dose, B. P. Sleckman, J. Han, A. L. Bredemeyer, A. Bendelac, and F. Gounari
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M. Locci, E. Draghici, F. Marangoni, M. Bosticardo, M. Catucci, A. Aiuti, C. Cancrini, L. Marodi, T. Espanol, R. G.M. Bredius, et al.
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K. Kawana, J. Matsumoto, S. Miura, L. Shen, Y. Kawana, T. Nagamatsu, T. Yasugi, T. Fujii, H. Yang, A. J. Quayle, et al.
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M. Felices and L. J. Berg
The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival
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B. B. Au-Yeung and D. J. Fowell
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A. J. Zullo, K. Benlagha, A. Bendelac, and E. J. Taparowsky
Sensitivity of NK1.1-Negative NKT Cells to Transgenic BATF Defines a Role for Activator Protein-1 in the Expansion and Maturation of Immature NKT Cells in the Thymus
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J. S. Bezbradica, T. Hill, A. K. Stanic, L. Van Kaer, and S. Joyce
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C. Borowski and A. Bendelac
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