Behar Lab Homepage
Immunity to
Mycobacterium tuberculosis
Contents
MY LAB IS LOOKING FOR POST-DOCTORAL APPLICANTS!
Research Interests
Immunity to Tuberculosis. It is estimated that 1/3 of the world’s population has been infected with Mycobacterium tuberculosis (Mtb). In the majority of infected people, the immune response is able to adequately control the infection, and consequently only 5-10% will develop clinical disease during their lifetime. My long-term goal is to understand the immunological basis for protective immunity. One way we are investigating this problem is to determine why different mouse strains differ in their susceptibility to tuberculosis. We have observed that certain susceptible mouse strains are unable to efficiently recruit T cells to the lung following infection with Mtb, and this failure likely contributes to increased mortality and morbidity of susceptible mice. Therefore, we are particularly interested in the early events leading to the initiation of the pulmonary immune response following respiratory Mtb infection. This includes establishing how T cells are recruited back to the lung once T cell priming occurs. Although BCG is used universally as a vaccine, its efficacy in preventing pulmonary tuberculosis is controversial. Most Mtb infected individuals develop long-lived immunity that contains the infection in a T cell-dependent manner. Thus, there is considerable interest in how different T cell subsets contribute to immunity and whether vaccination can stimulate protective T cells. Delineating the role of CD8+ T cells in host immunity to Mtb has been hindered by the paucity of antigens known to be recognized by CD8+ T cells. CD8+ T cells specific for culture filtrate protein-10 (CFP10) are found in infected people, indicating that CFP10 can prime CD8+ T cells after infection. Notably, CFP10 is encoded in the RD1 genetic locus, which is associated with Mtb virulence. The aim of our studies is to identify, enumerate and functionally characterize CFP10-specific CD8+ T cells that are elicited following pulmonary infection. We are also interested in the role of CD1d restricted NKT cells in microbial immunity. The CD1d protein is a member of the CD1 family of b2 microglobulin-associated proteins. In contrast to class I and II MHC molecules, CD1 proteins have evolved to present lipid and glycolipid molecules to T cells. While CD1a, -b, and –c (group I CD1 proteins) have been shown to present foreign microbial antigens to human abTCR+ T cells, CD1d-restricted T cells have been implicated in immunoregulation, and may be involved in microbial immunity, both in human disease and in mouse models. Our ultimate goal is to understand how the immune system contains Mtb and why impairment of cell mediated immunity leads to reactivation of tuberculous disease.
Recognition of CD1d presented antigens by T
cells. The CD1d protein is a
member of the CD1 family of b2 microglobulin-associated proteins. In contrast to class I and II MHC molecules,
CD1 proteins appear to have evolved to present lipid and glycolipid molecules
to T cells. While CD1a,
-b, and –c (group I CD1 proteins) have been shown to present foreign microbial
antigens to human abTCR+ T cells,
most CD1d restricted T cells described to date are autoreactive. CD1d reactive T cells have been strongly
implicated in immunoregulation of T
cell immune responses, and may be involved in the suppression of autoimmunity,
both in human disease and in mouse models.
Despite important correlations with autoimmune disease, the
physiologically relevant autoantigens
that are the likely targets of CD1d autoreactive T cells remain elusive. We are using traditional biochemical
approaches coupled with newly developed bioassays to purify and identify the
endogenous antigens presented by CD1d to autoreactive T cells. Mutagenesis of cloned TCRs
is being carried out to identify the critical contact residues in the CDR3
loops that interact with the lipid/CD1d complex. These investigations will enhance our
understanding of self-recognition of CD1d by T cells, and ultimately, will
provide insights into how these cells modulate immunity.
Contact Information
E-mail address
Office address
Samuel M.
Behar, M.D., Ph.D.
Division of Rheumatology, Immunology,
and Allergy
Brigham and Women's Hospital
Smith Building, Room 516
One Jimmy Fund Way
Boston, MA 02115
Office phone
(617) 525-1033 (voice)
(617) 525-1010 (FAX)
Current Projects
1. The
role of antigen specific CD8+ T cells in immunity to Mycobacterium tuberculosis
2. The role of CD1d
and NKT cells in immunity in microbial immunity.
3. Immunological differences between mice that are susceptible or resistant to tuberculosis.
4. Regulation
of T cell trafficking to the lung following infection with Mycobacterium tuberculosis.
5. The role of
pulmonary epithelial cells in immunity to Mycobacterium tuberculosis.
Last revised: August 30, 2005