The development of many autoimmune diseases has been etiologically linked to exposure to infectious agents. For example, a subset of patients with a history of Salmonella infection develop reactive arthritis. The persistence of bacterial antigen in arthritic tissue and the isolation of Salmonella or Yersinia reactive CD8+ T cells from the joints of patients with reactive arthritis support the etiological link between Gram-negative bacterial infection and autoimmune disease. Models proposed to account for the link between infection and autoimmunity include inflammation-induced presentation of cryptic self-epitopes, antigen persistence and molecular mimicry. Several studies support molecular mimicry as a mechanism for the involvement of class II epitopes in infectious disease-induced self-reactivity. Here, we have identified an immunodominant epitope derived from the S. typhimurium GroEL molecule. This epitope is presented by the mouse H2-T23-encoded class Ib molecule Qa-1 and was recognized by CD8+ cytotoxic T lymphocytes induced after natural infection. S. typhimurium-stimulated cytotoxic T lymphocytes recognizing the GroEL epitope cross-reacted with a peptide derived from mouse heat shock protein 60 and recognized stressed macrophages. Our results indicate involvement of MHC class Ib molecules in infection-induced autoimmune recognition and indicate a mechanism for the etiological link between Gram-negative bacterial infection and autoimmunity.

Previously, a peptide epitope derived from the Hsp 60 molecule of Salmonella that is presented by the major histocompatibility complex (MHC) class Ib molecule Qa-1 to CD8 ؉ cytotoxic T cells (CTLs) was described. In the present study we investigated the Salmonella-induced processing and presentation pathway for generating this Qa-1-restricted epitope. Live bacteria and, to a lesser extent, opsonized heat-killed bacteria are able to sensitize target cells for lysis by Salmonella-specific CTL. In contrast, heat-killed bacteria cannot sensitize target cells. Presentation of the Hsp 60 epitope appears independent of bacterial internalization, because cytochalasin D does not affect presentation. Moreover, Salmonella strains defective in the InvA or InvE operon, two critical components of the type III secretion pathway, are as efficient as wild-type Salmonella enterica serovar Typhimurium in sensitizing infected targets to lysis. Collectively, these results suggest the existence of a novel antigen-processing pathway in which exogenous antigens gain access to the cytosolic MHC class I processing machinery. Considering the abundant nature of bacterial Hsp 60 and the upregulation of this protein after Salmonella infection of eukaryotic cells, this mode of antigen presentation may be particularly relevant to understanding the host defense mechanisms against gram-negative bacteria.Class I molecules play a fundamental role in the activation of CD8 ϩ cytotoxic T cells (CTLs) during the generation of an adaptive immune response to intracellular pathogens (43). It has been generally accepted that the first step in the endogenous class I antigen presentation pathway is the hydrolysis of cytosolic proteins into peptides by the proteasome (41). These peptides are then selectively translocated into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) complex. As a result, this set of peptides is available to bind to the peptide-binding site of newly synthesized major histocompatibility complex (MHC) class I molecules in the ER. Once a stable complex of peptide, MHC class I molecule, and ␤-2 microglobulin is formed, the complex is transported to the plasma membrane and is available for recognition by and activation of peptide-specific CD8 ϩ T cells. In this manner the immune system can recognize host cells that have been altered by infection, mutation, or malignant transformation.Intracellular and extracellular bacterial pathogens can bind to and be internalized by professional antigen-presenting cells (APCs) (29). Many intracellular pathogens survive within host membrane-bound vesicles and, in some instances, replicate within these vesicles. Despite this subcellular localization, several examples have been described wherein bacterial antigens derived from intracellular bacteria gain access to the class I processing pathway for presentation by MHC class I to bacterium-specific CD8 ϩ effector T cells (reviewed in reference 21).The processing of bacterial antigens through the MHC class I pathway ...

Despite being a major group of intracellular pathogens, the role of class I-restricted T cells in the clearance of Gram-negative bacteria is not resolved. Using a murine typhoid model, a role for class I-restricted T cells in the immune response to the Gram-negative pathogen Salmonella typhimurium is revealed. Class I-deficient β2-microglobulin−/− mice show increased susceptibility to infection with S. typhimurium. Following infection, CD8+ CTLs specific for Salmonella-infected targets can be readily detected. The Salmonella-specific CTLs recognize infected H-2-mismatched targets, suggesting the involvement of shared class Ib molecules. Studies using transfectants expressing defined class Ia and class Ib molecules indicate the involvement of the class Ib molecule, Qa-1. Ab-blocking studies and the measurement of bacteria-specific CTL frequencies identified Qa-1 as a dominant restricting element. The Qa-1-restricted CTL recognition depends on TAP and proteasome functions. Surprisingly, Qa-1-restricted CTLs recognized cells infected with other closely related Gram-negative bacteria. Taken together, these observations indicate that Salmonella-specific CTLs recognize a cross-reactive epitope presented by Qa-1 molecules and, as such, may be novel targets for vaccine development.