Cellular mechanisms of antigen processing and the function of class I and II major histocompatibility complex molecules.

Harding, Clifford V.; Unanue, Emil R.

doi:10.1091/mbc.1.7.499

Cited by 55 publications

(20 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior to T-cell activation, however, antigen processing is necessary for a protein antigen to stimulate the specific T-cells; this processing consists of multiple steps of cellular events, i.e. internalization of proteins by antigen-presenting cells, reduction of the disulfide bond and unfolding of proteins, enzymatic digestion, and assembly of the generated peptides with major histocompatibility complex class II molecules (3,4). Proteases preferentially digest proteins in an unfolded state rather than those in a folded state (5-7); thus, the unfolding may be a crucial step for intracellular antigen processing.…”

Section: An Antigen-specific Cd4mentioning

confidence: 99%

Depression of T-cell Epitope Generation by Stabilizing Hen Lysozyme

So¹,

Ito²,

Koga³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

Conformational stability of proteins is an important factor that determines their resistance/susceptibility to proteolytic digestion. Intracellular proteolysis is the key step in antigen presentation events for protein antigens; hence, it is likely that increasing protein stability reduces the antigenicity of proteins. We prepared three hen egg white lysozyme derivatives possessing different stabilities by chemical modification to clarify the relationship between conformational stability and the antigenicity of the protein. One of the derivatives was conformationally unstabilized by removing one intramolecular disulfide bond, whereas the two others were stabilized by the addition of an intramolecular crosslink. The antigenicity of these derivatives was evaluated using hen egg white lysozyme-specific T-cell hybridoma cells and a B-lymphoma cell line, A20, as antigen-presenting cells. With an increase in conformational stability, the T-cell response decreased. However, the reduction was not derived from the inefficiency of internalization to A20 cells nor the alteration of antigenicity by chemical modifications. Moreover, from analyses of their susceptibility to proteolysis and the kinetics of presentation of the T-cell epitope, it was confirmed that increasing protein stability led to the depression of T-cell epitope generation by increasing resistance to proteolysis. These results have an important implication in devising a new strategy for manipulating T-cell response by the stability of protein antigen. An antigen-specific CD4ϩ T-cell recognizes an antigen-derived peptide that is mounted on a major histocompatibility complex class II molecule on a cell surface of antigen-presenting cells, via its antigen receptor (1, 2). Therefore, the conformation of protein antigens is unlikely to have any role in the step of T-cell recognition. Prior to T-cell activation, however, antigen processing is necessary for a protein antigen to stimulate the specific T-cells; this processing consists of multiple steps of cellular events, i.e. internalization of proteins by antigen-presenting cells, reduction of the disulfide bond and unfolding of proteins, enzymatic digestion, and assembly of the generated peptides with major histocompatibility complex class II molecules (3, 4). Proteases preferentially digest proteins in an unfolded state rather than those in a folded state (5-7); thus, the unfolding may be a crucial step for intracellular antigen processing. In this context, we can expect that depression of protein unfolding by increasing protein stability would reduce the antigenicity of proteins for T-cells.Several reports have demonstrated a relationship between increased antigenicity and the decreased stability of proteins (8 -10). However, the influence of protein stability on the antigenicity remains unknown. To address this issue, we prepared three derivatives of hen egg white lysozyme (HEL) 1 possessing different conformational stabilities (see Table I). A three-disulfide derivative of HEL, S-carboxymethylated HEL at Cys ...

show abstract

Section: An Antigen-specific Cd4mentioning

confidence: 99%

Depression of T-cell Epitope Generation by Stabilizing Hen Lysozyme

So¹,

Ito²,

Koga³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Protein Ags are incorporated into APCs and then are degraded by endosomal proteases (13)(14)(15). The peptides are then mounted on MHC class II molecules on the surfaces of APCs (16,17).…”

mentioning

confidence: 99%

A Protein’s Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins

Ohkuri

Nagatomo

Oda

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…T he MHC class II molecules are heterodimeric complexes that display the foreign antigenic peptides on the cell surface of APCs to CD4 ϩ T cells (1)(2)(3). MHC class II synthesis and assembly begins in the endoplasmic reticulum (ER), 3 with the noncovalent association of the ␣-and ␤-chains with trimers of the invariant chain (Ii) (4).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…MHC class II synthesis and assembly begins in the endoplasmic reticulum (ER), 3 with the noncovalent association of the ␣-and ␤-chains with trimers of the invariant chain (Ii) (4). Briefly, three ␣␤ dimers bind sequentially to a trimer of the Ii to form a nonameric complex (␣␤Ii) 3 (5)(6)(7), which then exits the ER. After being transported to the trans-Golgi, the ␣␤Ii complex is diverted from the secretory pathway to the endocytic system (8 -11) and ultimately to acidic endosome/lysosome-like structures called MHC class II compartments (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Preferential Th1 Immune Response in Invariant Chain-Deficient Mice

Topilski

Harmelin

Flavell

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

MHC class II molecules associate with the invariant chain (Ii) molecule during biosynthesis. Ii facilitates the folding of class II molecules, interferes with their peptide association, and is involved in MHC class II transport. In this study, we have investigated the in vitro and in vivo immune response of Ii-deficient mice (Ii−/−). Our results have demonstrated that CD4+ T cells from Ii−/− mice proliferate normally in vitro after in vivo immunization with protein Ags. However, cytokine secretion profiles of Ag-primed CD4+ T cells from Ii−/− mice differ from CD4+ T cells from wild-type mice. Whereas cells from wild-type mice secrete IFN-γ and IL-4, cells from Ii−/− mice secrete mostly IFN-γ. Moreover, Ii−/− mice exhibit a normal Th1 response in the delayed-type hypersensitivity and trinitrobenzene sulfonic acid colitis models; however, these mice lack an in vivo Th2 response, as demonstrated in the asthma model. Therefore, we suggest that defective Ag presentation in Ii−/− mice leads selectively to a Th1 effector response.

show abstract

Cellular mechanisms of antigen processing and the function of class I and II major histocompatibility complex molecules.

Cited by 55 publications

References 82 publications

Depression of T-cell Epitope Generation by Stabilizing Hen Lysozyme

Depression of T-cell Epitope Generation by Stabilizing Hen Lysozyme

A Protein’s Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins

Preferential Th1 Immune Response in Invariant Chain-Deficient Mice

Contact Info

Product

Resources

About