Ph.D.: 1998, The University of Dundee, Scotland, U.K.
Awards and Honors:
Presbyterian Health Foundation Presidential Professorship
Member, NIH Vaccines against Microbial Diseases (VMD) Study Section
Member, American Association of Immunologists Program Committee
Dartmouth College and Medical School
NKT cells and regulation of humoral immune responses
Immunology for Graduate College, College of Medicine, and Department of Microbiology and Immunology
Office: BMSB 1019
Boosting humoral immunity to toxins by activation of CD1d-restricted NKT cells
Vaccines that stimulate long-term humoral (antibody-mediated) immunity against bacterial toxins provide long-term protection against disease. Diphtheria, tetanus, whooping cough, 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 pathogen-derived toxins. For example, pathogens that secrete toxins such as Bacillus anthracis and Clostridium difficile pose significant dangers to human health.
To address the challenges inherent in developing vaccines against such pathogens and their toxins, it is important 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 (NKT) greatly enhances primary and recall responses to bacterial antigens in vivo. Importantly, 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 NKT cells might be effective for all individuals.
Further study by our group over the past 5 years has revealed that direct interaction between B cells expressing CD1d/glycolipid complexes on the cell surface and the T cell antigen receptor is essential for these effects. We have also demonstrated that NKT cells have several effects on the induction and maintenance of B cell memory and long-lived plasma cells, two essential elements of persistent humoral immunity.
We are currently focused on understanding the detailed mechanisms by which CD1d-expressing B cells stimulate distinct functional sub-sets of NKT cells to enhance humoral responses to bacterial toxins. These approaches will provide the necessary insights for the development of novel vaccines that activate NKT cells.
Current Lab Personnel:
Souwelimatou Amadou Amani, Graduate Student
Gillian Lang MPH, Research Associate
Binu Shrestha Ph.D., Postdoctoral Fellow
- N.S. Butler, M.L. Lang, M. Richer. (2016) T cell fates zipped up: How the BACH2 basic leucine zipper transcriptional repressor directs T cell differentiation and function. Brief Reviews, Journal of Immunology, 197, *** (in press).
- T.S. Devera, J.L Lanis, G.A. Lang, P.R. Rampuria, G.A. Lang, J.D. Ballard and M.L. Lang (2016) Memory B cells encode neutralizing antibody specific for Toxin B from the Clostridium difficile strains VPI 10463 and NAP1/BI/027, but with superior in vitro protection against VPI 10463. Infection and Immunity, 84, 194-204.
- T.S. Devera, S.K. Joshi, J.D. Ballard and M.L. Lang (2015) Immunization with anthrax protective antigen vaccine limits cardiotoxicity but not hepatotoxicity associated with lethal toxin challenge Toxins 7: 2371-2384.
- P. Rampuria and M.L. Lang (2015) CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation. International Immunology 27(5):253-263.
- M.L. Lang (2014) The importance of B cell CD1d expression for humoral immunity (review/editorial) In press Expert Review of Vaccines 20: 1-4
- S.K. Joshi and M.L. Lang (2013) Fine tuning a well-oiled machine: Influence of NK1.1 and NKG2D on NKT cell development and function. International Immunopharmacology 17: 260-266.
- H.B. Shah, S.K. Joshi, P. Rampuria, G.A. Lang, W. Stohl and M.L. Lang (2013) BAFF- and APRIL-dependent maintenance of Ab titers after immunization with T-dependent Ag and CD1d-binding ligand. Journal of Immunology 191:1154-
- S.K. Joshi, G.A. Lang, S. Kovats and M.L. Lang (2012) Differential Contribution of Dendritic Cell CD1d to NKT Cell-Enhanced Humoral Immunity and CD8+ T Cell Activation. Journal of Leukocyte Biology 91: 783-790.
- T.S. Devera, S.K. Joshi, L.M. Aye, G.A. Lang, J.D. Ballard and M.L. Lang(2011) Regulation of anthrax toxin-specific antibody titers by Natural Killer T cell-derived IL-4 and IFNγ. PLOS One 6(8): e23817. doi:10.1371/journal.pone.0023817
- G.A. Lang, A.M. Johnson, T.S. Devera, S.K. Joshi, and M.L. Lang (2011) Reduction of CD1d expression in vivo minimally affects NKT-enhanced Ab production but boosts B cell memory. International Immunology.23: 251-260.
- H.B. Shah, S.K. Joshi, and M.L. Lang. (2011) CD40L-null NKT cells provide B cell help for specific antibody responses. Vaccine. 29: 9132-9136
- H.B. Shah, T.S. Devera, G.A. Lang, P. Rampuria and M.L. Lang (2012) Type II NKT cells facilitate Alum-sensing and humoral immunity. Journal of Leukocyte Biology. 92:883-893.
- T.S. Devera, L.M. Aye, G.A. Lang, S.K. Joshi, J.D. Ballard and M.L. Lang (2010) CD1d-dependent B cell help by NKT cells leads to enhanced and sustained production of Bacillus anthracis lethal toxin-neutralizing antibodies. Infection and Immunity. 78: 1610-1617.
- S.K. Joshi, G.A. Lang, J.L. Larabee, T.S. Devera, L.M. Aye, H.B. Shah, J.D. Ballard and M.L. Lang(2009) Bacillus anthracis lethal toxin disrupts TCR-signaling in CD1d-restricted NKT cells in vivo leading to functional anergy. PLOS Pathogens. 5: 1-10.
- M.L. Lang (2009) How do NKT cells help B cells? (review) Expert Review of Vaccines. 8: 1131-1131
- T.S. Devera, G.A. Lang, H.B. Shah and M.L. Lang (2008) Glycolipid-activated NKT cells support the induction of persistent plasma cell responses and sustained antibody titer. European Journal of Immunology 38: 1001-1011.
- G.A. Lang, T.S. Devera and M.L. Lang (2008) Requirement for CD1d expression by B cells to stimulate NKT-enhanced antibody production. Blood 111:2158-2162.
- M.L. Lang and A. Glatman-Freedman. (2006). Do CD1-restricted T cells contribute to antibody-mediated immunity against Mycobacterium tuberculosis? Infection and Immunity 74: 803-809.
- G.A. Lang, M. Exley, and M.L. Lang. (2006) The CD1d-binding glycolipid α-galactosylceramide enhances humoral immunity to T-dependent and T-independent antigen in a CD1d-dependent manner. Immunology 119: 116-125.
- G.A. Lang, P. Illirianov, G.S. Besra and M.L. Lang. (2005). BCR-targeting of α-Galactosylceramide leads to enhanced presentation on CD1d and requires transport of BCR to CD1d-containing endocytic compartments. International Immunology 17: 899-908.
- G.A. Lang, S. Maltsev, G.S. Besra and M.L. Lang. (2004). Presentation of α-Galactosylceramide by murine CD1d to NKT cells is facilitated by plasma membrane glycolipid rafts. Immunology 112:386-396.