Are primary alloresponses truly primary?

Lombardi, Giovanna; Sidhu, Sid; Daly, Maria C.; Batchelor, J. R.; Makgoba, William; Lechler, Robert I.

doi:10.1093/intimm/2.1.9

Cited by 125 publications

(80 citation statements)

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“…MHC-bound self-peptides influence development of immature thymocytes (42,43), and mature T cells interact with Ags from foreign pathogens presented by self-MHC or self-peptides presented by foreign MHC molecules. The alloreactive T cells can originate from both naive and memory T cell populations (44). However, involvement of memory T cells need not imply previous alloimmunization by pregnancy, blood transfusion, or allogeneic tissue transplantation.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers

Whitelegg

Oosten²,

Jordan³

et al. 2005

The Journal of Immunology

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Alloreactive T cells are involved in injurious graft rejection and graft-vs-host disease. However, they can also evoke beneficial responses to tumor Ags restricted by foreign MHC molecules. Manipulation of these alloreactivities requires information on the basis of T cell allorecognition. The vigorous T cell response to foreign MHC molecules may arise from peptide-independent recognition of polymorphic residues of foreign MHC molecules or peptide-specific recognition of novel peptides presented by foreign MHC molecules. We investigated CD8+ T cell allorecognition using recombinant HLA class I/peptide complexes. Peptide-specific allorecognition was examined using tetramers of HLA-A*0201 representing five peptides derived from ubiquitously expressed self-proteins that are known to bind endogenously to HLA-A*0201. Distinct subsets of CD8+ T cells specific for each HLA-A*0201/peptide combination were detected within four in vitro-stimulated T cell populations specific for foreign HLA-A*0201. Peptide-independent allorecognition was investigated using artificial Ag-presenting constructs (aAPCs) coated with CD54, CD80, and functional densities of a single HLA-A*0201/peptide combination for four different peptides. None of the four T cell populations specific for foreign HLA-A*0201 were stimulated by the aAPCs, whereas they did produce IFN-γ upon stimulation with cells naturally expressing HLA-A*0201. Thus, aAPCs did not stimulate putative peptide-independent allorestricted T cells. The results show that these alloreactive populations comprise subsets of T cells, each specific for a self-peptide presented by foreign class I molecules, with no evidence of peptide-independent components.

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Section: Discussionmentioning

confidence: 99%

Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers

Whitelegg

Oosten²,

Jordan³

et al. 2005

The Journal of Immunology

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“…More than 15 years ago, Lombardi et al (44) explored the contribution of naive and memory population to the allogeneic MLR in an article provocatively entitled "Are primary alloresponses truly primary?" Subsequently, direct evidence for cross-reactivity has been provided by studies showing that human clones specific for an EBV peptide presented in the context of HLA-B8 also recognize three common allogeneic HLA molecules (B14, B44, or B35) (45)(46)(47).…”

Section: Heterologous Immunity: Good News For Protective Immunity Butmentioning

confidence: 99%

Patients, Pathogens, and Protective Immunity: The Relevance of Virus-Induced Alloreactivity in Transplantation

Koehn

Gangappa

Miller

et al. 2006

The Journal of Immunology

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Successful transplantation requires the establishment of an ongoing state in which there is simultaneous inhibition of the undesired T cell-dependent rejection response and yet retention of the ability to develop effective cell-mediated primary and memory responses to pathogens. The complexity of attaining such a precarious state is underscored by the growing body of evidence that alloreactivity can be profoundly influenced by infections that occur before, concurrent with, or subsequent to an organ transplant. In this review, we explore the growing list of mechanisms that have been identified by which pathogen-host interactions might influence rejection, including the degeneracy of TCR recognition leading to cross-reactive immune responses, the effects of pathogens on innate immune mechanisms, and the potential impact of virally induced lymphopenia.

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“…Two sets of anti-DR1 alloreactive T cell clones were used as tools to address the influence of Ii on peptide occupancy of MHC class II molecules in intact cells. The first was generated against allogeneic, DR1 ϩ Ii ϩ HLA-DM ϩ PBMC (22,23). The majority of these clones (4͞6) were poorly stimulated by M1.DR1 and none were stimulated by M1.DR1.Ii (clones L9, K18, G3, and G8, Figs.…”

Section: M1 Cells Do Not Constitutively Express Dr II or Hla-dm Molmentioning

confidence: 99%

In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

Lightstone¹,

Hargreaves²,

Bobek³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The independent inf luences of invariant chain (Ii) and HLA-DM molecules on the array of naturally processed peptides displayed by HLA-DR molecules were studied using transfected cell lines. Major histocompatibility complex (MHC) class II molecules present peptide antigens to MHC class II-restricted CD4 ϩ T cells. The peptides presented are usually derived from internalized exogenous or membrane-bound proteins (1) which are unfolded, denatured, and degraded within the progressively acidic endosomal pathway. Class II molecules are assembled in the endoplasmic reticulum (ER), where they associate noncovalently with the invariant chain (Ii), a type 2 transmembrane protein (reviewed in ref.2). The CLIP region of Ii (amino acids 81-104) binds in the groove of nascent MHC class II molecules, thereby inhibiting the binding of peptides in the ER (3-5). An endosomal targeting motif within the amino terminus of the p33 form of Ii directs the Ii-class II complexes to specialized endosomal compartments, MIIC (6, 7). Here, Ii is sequentially degraded by proteases, and the catalytic activity of HLA-DM promotes exchange of CLIP for peptides derived from endocytosed proteins (8-11).In the absence of Ii, as shown in Ii knockout mice (Ii 0/0 ), few class II molecules reach the cell surface, as most are retained in the ER and degraded (12, 13). The studies of antigen presentation by Ii-negative (Ii Ϫ ) cells reported to date have largely used T cell clones or hybridomas raised against conventional antigen-presenting cells (APC) as responders. The results of such studies have shown that a degree of overlap exists between the peptides displayed by MHC class II molecules expressed in the presence and the absence of Ii (for example, see ref. 14). However, this approach does not inform whether the complete or relative absence of Ii leads to the display of novel peptide epitopes by MHC class II molecules, an important issue if circumstances can arise in vivo in which Ii is limiting in MHC class II ϩ cells.In this study we used alloreactive T cell clones as probes of peptide occupancy of class II molecules expressed in the presence or absence of Ii and HLA-DM on the basis that anti-MHC allorecognition generally involves the corecognition of the allogeneic MHC molecule and bound peptide (for review see ref. 15). The results suggest that in the absence of Ii, MHC class II molecules display a distinct array of peptides. Furthermore, HLA-DM influenced allorecognition of DR molecules in the absence of Ii, suggesting that HLA-DM can influence MHC class II peptide occupancy independently of Ii. Taken together, these findings support the prediction that discordant regulation of MHC class II, Ii, and HLA-DM molecules in vivo, as has been observed in bone marrow macrophages (16) and in gut epithelial cells (17) for MHC and Ii, could lead to the display of self-peptides to which the T cell repertoire is not tolerant.

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Are primary alloresponses truly primary?

Cited by 125 publications

References 0 publications

Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers

Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers

Patients, Pathogens, and Protective Immunity: The Relevance of Virus-Induced Alloreactivity in Transplantation

In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

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