Boosting humoral immunity to pathogens by activation of CD1d-restricted NKT cells

Vaccines that stimulate long-term humoral (antibody-mediated) immunity against bacterial pathogens provide long-term protection against disease. Diphtheria, tetanus, whooping cough, scarlet fever and many other diseases are now relatively rare. Despite the enormous positive impact of antibody-inducing vaccines on public health, we still do not have effective vaccines for all pathogenic bacteria. Pathogens that result in meningitis, tuberculosis and other diseases still pose significant dangers. Furthermore, there is a need for improved vaccines against bacterial agents considered to be bioterrorism threats.

How do we address the challenges inherent in developing vaccines against such pathogens? One way is to improve our understanding of the induction and maintenance of humoral immunity at a mechanistic level. We have discovered that activation of invariant Natural Killer-like T cells (inv. NKT) greatly enhances primary and recall responses to bacterial antigens in vivo. Preliminary studies in the Lang laboratory indicate that NKT cells have several effects on the induction and maintenance of humoral immunity. Importantly, inv. NKT cells are restricted by MHC class I-related CD1d molecules presenting glycolipid antigens. Since CD1d is non-polymorphic, a vaccine containing CD1d-binding glycolipid antigens that appropriately activates inv. NKT cells might be effective for all individuals.

We are currently focused on understanding the mechanisms by which CD1d-expressing cells stimulate NKT cells to enhance humoral responses to bacterial pathogens. Our results indicate that NKT cells impact B cell memory and experiments are underway to determine how this is achieved. Furthermore, in partnership with the COBRE proteomics facility we are working towards discovery of novel products produced by CD1d-expressing cells and NKT cells. These approaches will provide the necessary insights for the future development of novel vaccines that activate NKT cells.

1:  Lang GA, Exley MA, Lang ML.  The CD1d-binding glycolipid alpha-galactosylceramide enhances humoral immunity to T-dependent and T-independent antigen in a CD1d-dependent manner. Immunology. 2006 Sep;119(1):116-25. Epub 2006 Jun 22. PMID: 16792697 [PubMed - in process]

2:  Pleass RJ, Lang ML, Kerr MA, Woof JM.  IgA is a more potent inducer of NADPH oxidase activation and degranulation in blood eosinophils than IgE. Mol Immunol. 2007 Feb;44(6):1401-8. Epub 2006 Jun 13. PMID: 16777227 [PubMed - in process]

3:  Lang GA, Lang ML.  Protein kinase Balpha is required for vesicle trafficking and class II presentation of IgA Fc receptor (CD89)-targeted antigen. J Immunol. 2006 Apr 1;176(7):3987-94. PMID: 16547233 [PubMed - indexed for MEDLINE]

4:  Lang ML, Glatman-Freedman A.  Do CD1-restricted T cells contribute to antibody-mediated immunity against Mycobacterium tuberculosis?Infect Immun. 2006 Feb;74(2):803-9. Review. No abstract available. PMID: 16428722 [PubMed - indexed for MEDLINE]

5:  Lang GA, Illarionov PA, Glatman-Freedman A, Besra GS, Lang ML.  BCR targeting of biotin-{alpha}-galactosylceramide leads to enhancedpresentation on CD1d and requires transport of BCR to CD1d-containing endocytic compartments. Int Immunol. 2005 Jul;17(7):899-908. Epub 2005 Jun 20. PMID: 15967785 [PubMed - indexed for MEDLINE]

6:  Chen YW, Lang ML, Wade WF.  Protein kinase C-alpha and -delta are required for FcalphaR (CD89) trafficking to MHC class II compartments and FcalphaR-mediated antigen presentation.Traffic. 2004 Aug;5(8):577-94. PMID: 15260828 [PubMed - indexed for MEDLINE]

7:  Lang GA, Maltsev SD, Besra GS, Lang ML.  Presentation of alpha-galactosylceramide by murine CD1d to natural killer T cells is facilitated by plasma membrane glycolipid rafts.Immunology. 2004 Jul;112(3):386-96. PMID: 15196206 [PubMed - indexed for MEDLINE]

8:  Lang ML, Chen YW, Shen L, Gao H, Lang GA, Wade TK, Wade WF.  IgA Fc receptor (FcalphaR) cross-linking recruits tyrosine kinases,phosphoinositide kinases and serine/threonine kinases to glycolipid rafts.Biochem J. 2002 Jun 1;364(Pt 2):517-25. PMID: 12023895 [PubMed - indexed for MEDLINE]

9:  Lang ML, Shen L, Gao H, Cusack WF, Lang GA, Wade WF.  Fc alpha receptor cross-linking causes translocation ofphosphatidylinositol-dependent protein kinase 1 and protein kinase B alpha to MHC class II peptide-loading-like compartments.J Immunol. 2001 May 1;166(9):5585-93. PMID: 11313398 [PubMed - indexed for MEDLINE]

10:  Shen L, van Egmond M, Siemasko K, Gao H, Wade T, Lang ML, Clark M, van De Winkel JG, Wade WF.  Presentation of ovalbumin internalized via the immunoglobulin-A Fc receptor is enhanced through Fc receptor gamma-chain signaling.Blood. 2001 Jan 1;97(1):205-13. PMID: 11133762 [PubMed - indexed for MEDLINE]

11:  Lang ML, Kerr MA.  Characterization of FcalphaR-triggered Ca(2+) signals: role in neutrophil NADPH oxidase activation.Biochem Biophys Res Commun. 2000 Sep 24;276(2):749-55. PMID: 11027542 [PubMed - indexed for MEDLINE]

12:  Shen L, Lang ML, Wade WF.  The ins and outs of getting in: structures and signals that enhance BCR or Fc receptor-mediated antigen presentation.Immunopharmacology. 2000 Sep;49(3):227-40. Review. PMID: 10996020 [PubMed - indexed for MEDLINE]

13:  Lang ML, Yadati S, Seeley ES, Nydam T, Wade TK, Gabriel JL, Yeaman G,Barisas BG, Wade WF.  Mutations in specific I-A(k) alpha(2) and beta(2) domain residues affect surface expression.Int Immunol. 2000 Jun;12(6):777-86. PMID: 10837405 [PubMed - indexed for MEDLINE]

14:  Lang ML, Kerr MA.  Neutrophil NADPH oxidase does not assemble on macropinocytic vacuole membranes.Immunol Lett. 2000 Apr 3;72(1):1-6. PMID: 10789674 [PubMed - indexed for MEDLINE]

15:  Lang ML, Shen L, Wade WF.  Gamma-chain dependent recruitment of tyrosine kinases to membrane rafts by the human IgA receptor Fc alpha R.J Immunol. 1999 Nov 15;163(10):5391-8. PMID: 10553064 [PubMed - indexed for MEDLINE]

16:  Lang ML, Kerr MA.  Neutrophil Fc receptors signal through PI 3-kinase to trigger a respiratory burst.Biochem Soc Trans. 1997 Nov;25(4):S603. No abstract available. PMID: 9450031 [PubMed - indexed for MEDLINE]

17:  Lang ML, Glennie MJ, Kerr MA.  Human neutrophil Fc alpha R and Fc gamma RIIa but not Fc gamma RIIIb generate intracellular calcium signals which trigger the respiratory burst.Biochem Soc Trans. 1997 May;25(2):333S. No abstract available. PMID: 9191378 [PubMed - indexed for MEDLINE]

18:  Furrie E, Bonner BC, Hutchings A, Lang ML, Kerr MA.  Differential activation of peripheral blood monocytes using various forms ofhuman IgA.Biochem Soc Trans. 1997 May;25(2):332S. No abstract available. PMID: 9191377 [PubMed - indexed for MEDLINE]

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