H2-M3<sup>wt</sup>-restricted, <i>Listeria monocytogenes</i>-specific CD8 T cells recognize a novel, hydrophobic, protease-resistant, periodate-sensitive antigen

Effective protection against Listeria monocytogenes requires Ag-specific CD8+ T cells. A substantial proportion of CD8+ T cells activated during L. monocytogenes infection of C57BL/6 mice are restricted by the MHC class Ib molecule H2-M3. In this study, an H2-M3-restricted CD8+ T cell clone specific for a known H2-M3 epitope (fMIGWII) was generated from L. monocytogenes-infected mice. The clone was cytotoxic, produced IFN-γ, and could mediate strong protection against L. monocytogenes when transferred to infected mice. Macrophages pulsed with heat-killed Listeriae presented Ag to the clone in a TAP-independent manner. Both TAP-independent and -dependent processing occurred in vivo, as TAP-deficient mice infected with L. monocytogenes were partially protected by adoptive transfer of the clone. This is the first example of CD8+ T cell-mediated, TAP-independent protection against a pathogen in vivo, confirming the importance of alternative MHC class I processing pathways in the antibacterial immunity.

Section: Discussionsupporting

confidence: 83%

Partially TAP-Independent Protection AgainstListeria monocytogenesby H2-M3-Restricted CD8+ T Cells

Rolph

Kaufmann

2000

“…Glycolipid bacterial Ags may induce cytolytic activity by H2-M3-restricted CD8 ϩ T cells (15). To prove that other peptides, rather than lipids or glycolipids, primed fMIGWII-specific CD8 ϩ T cells during infection with L. monocytogenes fMIG neg , we subjected HPLC fractions from L. monocytogenes fMIG neg culture supernatants that induced the strongest cytolytic activity to enzymatic digestion.…”

Section: Discussionmentioning

confidence: 99%

“…However, the heat-killed L. monocytogenes-associated Ag was reported to be highly protease resistant, but periodate sensitive, suggesting that it contains a carbohydrate component (15). Subsequently, it was shown that the heat-killed L. monocytogenes-associated Ag consists of a complex of immunogenic fMIGWII associated with bacterial cardiolipin A (34).…”

Section: Fmigwii-specific Cd8 ϩ T Cells Are Also Primed By Peptides Wmentioning

confidence: 99%

“…In the setting of murine infection with Listeria monocytogenes, three H2-M3-restricted peptides, fMIGWII (11), fMIVIL (Fr38) (12), and fMIVTLF (13), have been identified (11,14). Although most recent studies have demonstrated peptide presentation, one study suggested that bacterial glycolipids may be presented by H2-M3 to L. monocytogenes-specific CD8 ϩ T cells (15).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Promiscuity of MHC Class Ib-Restricted T Cell Responses

Ploß

Lauvau

Contos

et al. 2003

Murine infection with the Gram-positive intracellular bacterium Listeria monocytogenes activates CD8+ T cells that recognize bacterially derived N-formyl methionine peptides in the context of H2-M3 MHC class Ib molecules. Three peptides, fMIGWII, fMIVIL, and fMIVTLF, are targets of L. monocytogenes-specific CD8+ T cells. To investigate epitope cross-recognition by H2-M3-restricted CD8+ T cells, we deleted the sequence encoding fMIGWII from a virulent strain of L. monocytogenes. Infection with fMIGWII-deficient L. monocytogenes unexpectedly primed CD8+ T cells that stain with fMIGWII/H2-M3 tetramers and lyse fMIGWII-coated target cells in vivo. Because the fMIGWII sequence is nonredundant, we speculated that other bacterially derived Ags are priming these responses. HPLC peptide fractionation of bacterial culture supernatants revealed several distinct L. monocytogenes-derived peptides that are recognized by fMIGWII-specific T cells. Our results demonstrate that the dominant H2-M3-restricted CD8+ T cell population, although reactive with fMIGWII, is primed by other, non-fMIGWII peptides derived from L. monocytogenes. Although this degree of Ag receptor promiscuity is unusual for the adaptive immune system, it may be a more common feature of T cell responses restricted by nonpolymorphic MHC class Ib molecules.

“…CD4 Ab had minimal effect on the response of LCD4.1 or LCD4.3 to M. leprae (Fig. 8, A and B), whereas the Ab inhibited the proliferation of an HLA-DRrestricted T cell line, D103-5 (45,46), by 83% (Fig. 8C).…”

Section: Cd1-restricted T Cellsmentioning

confidence: 98%

Evidence for Human CD4+ T Cells in the CD1-Restricted Repertoire: Derivation of Mycobacteria-Reactive T Cells from Leprosy Lesions

Sieling¹,

Ochoa²,

Jullien

et al. 2000

Both the CD4−CD8− (double negative) and CD4−CD8+ T cell lineages have been shown to contain T cells which recognize microbial lipid and glycolipid Ags in the context of human CD1 molecules. To determine whether T cells expressing the CD4 coreceptor could recognize Ag in the context of CD1, we derived CD4+ T cell lines from the lesions of leprosy patients. We identified three CD4+ Mycobacterium leprae-reactive, CD1-restricted T cell lines: two CD1b restricted and one CD1c restricted. These T cell lines recognize mycobacterial Ags, one of which has not been previously described for CD1-restricted T cells. The response of CD4+ CD1-restricted T cells, unlike MHC class II-restricted T cells, was not inhibited by anti-CD4 mAb, suggesting that the CD4 coreceptor does not impact positive or negative selection of CD1-restricted T cells. The CD4+ CD1-restricted T cell lines produced IFN-γ and GM-CSF, the Th1 pattern of cytokines required for cell-mediated immunity against intracellular pathogens, but no detectable IL-4. The existence of CD4+ CD1-restricted T cells that produce a Th1 cytokine pattern suggests a contributory role in immunity to mycobacterial infection.