The Cross‐priming Pathway: A Portrait of an Intricate Immune System

Basta, Sameh; Alatery, Attiya

doi:10.1111/j.1365-3083.2007.01909.x

Cited by 59 publications

(59 citation statements)

References 103 publications

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“…Because MBP crosspresentation by TECs occurs only in a nongrafted thymus, and TECs do not acquire classic MBP from BM-derived cells, it is likely that classic MBP is acquired directly from myelin in situ and that this access is disrupted in the thymus graft. This source is consistent with studies indicating that long-lived, stable proteins, rather than peptides, are the predominant source of crosspriming antigen in vivo (28,29). Acquisition of cell or membrane-associated protein occurs via phagosomes, and crosspresentation requires active alkalization of the phagosome to prevent protein degradation before antigen export to the cytoplasm (26).…”

Section: Discussionsupporting

confidence: 73%

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

Perchellet¹,

Brabb

Goverman³

2008

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

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Central tolerance plays a critical role in eliminating self-reactive T cells specific for peripheral antigens. Here we show that central tolerance of MHC class I-restricted T cells specific for classic myelin basic protein (MBP), a component of the myelin sheath, is mediated by both bone marrow (BM)-derived and nonBM-derived cells. Unexpectedly, BM-derived cells induce tolerance directly by using classic MBP that they synthesize, whereas nonBM-derived cells mediate tolerance by crosspresenting classic MBP acquired from an exogenous source. Thus, tolerance to tissue-specific antigens can involve multiple cell types and mechanisms in the thymus, which may account for the limited spectrum of autoimmune syndromes observed when expression of tissue-specific antigens is impaired only in thymic epithelial cells.autoimmunity ͉ EAE ͉ multiple sclerosis D efining the mechanisms that maintain tolerance to tissuespecific antigens (TSAs) is critical for understanding the pathogenesis of organ-specific autoimmune diseases such as multiple sclerosis (MS). Tolerance of many TSAs occurs in the thymus and is facilitated by medullary thymic epithelial cells (mTECs) that promiscuously express a broad range of TSAs (1). TSAs synthesized and presented by mTECs can induce tolerance in the MHC class I and II pathways (2, 3). In addition, bone marrow (BM)-derived cells can acquire TSAs from mTECs and induce both CD4 ϩ and CD8 ϩ T cell tolerance (2, 4). However, in vivo studies indicate that, under physiological conditions, only BM-derived cells acquire sufficient TSA from exogenous sources to negatively select MHC class II-restricted T cells (3,5).We investigated the mechanisms that induce central tolerance to myelin basic protein (MBP), which is believed to be targeted by self-reactive T cells in MS. The genetic organization of the MBP locus may influence how tolerance is induced to this self-antigen. The MBP locus encodes two separate protein families that are transcribed by using different promoters, both of which generate multiple isoforms via alternative splicing (6). One family consists of MBP isoforms that are incorporated into myelin (classic MBP) and are considered TSAs because of their restricted expression in myelin-forming cells. Proteins in the other family (golli MBP) modulate calcium influx (7,8) and are expressed in the nervous system, thymus, and peripheral lymphoid tissues (6). Although the two families differ functionally, classic and golli MBP are immunologically related because they contain stretches of identical amino acid sequence because of exon sharing (6). Thus, expression of golli MBP in the thymus could mediate negative selection of many classic MBP-specific T cells.We sought to define tolerance mechanisms for CD4 ϩ and CD8 ϩ MBP-specific T cells because both subsets mediate autoimmunity (5, 9, 10). We previously found that CD4 ϩ MHC class II-restricted T cells specific for MBP121-140, an epitope present in classic but not golli MBP, undergo central tolerance mediated by BM-derived cells that acquire classic ...

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Section: Discussionsupporting

confidence: 73%

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

Perchellet¹,

Brabb

Goverman³

2008

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

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“…Induction of protective immune responses against viruses or tumors can be achieved via cross-priming [4][5][6]. In this study, we employed the LCMV infection model to study how crosspresentation of multiple epitopes translates when studying cross-priming.…”

Section: Discussionmentioning

confidence: 99%

“…The priming of CTL is initiated by BM-derived professional APC (pAPC) [1][2][3], and is achieved via endogenous ''direct-presentation'' and exogenous ''cross-presentation'' [4][5][6]. The contribution of multiple epitopes from viral proteins to the cross-presentation pathway after infections is not well understood.…”

Section: Introductionmentioning

confidence: 99%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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“…This dichotomy in antigen presentation, however, is not absolute. Extracellular antigens may be presented on MHC class I by a pathway known as cross-priming [3]. Conversely, intracellular antigens may be presented on MHC class II by an endogenous presentation pathway [4].…”

Section: Introductionmentioning

confidence: 99%

Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1‐mediated nuclear export

Riedel

Nimmerjahn²,

Burdach

et al. 2008

Eur J Immunol

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Accumulating evidence suggests that intracellular antigens are endogenously presented on MHC class II, but it is still unknown whether antigens within different subcellular compartments are presented with similar efficiency, and via the same or different pathways. We have previously shown that endogenous MHC class II presentation of the cytosolic bacterial antigen neomycin phosphotransferase II (NeoR) is mediated by autophagy. Here, we addressed whether secluding NeoR from this cytoplasmic pathway by directing the protein into the cell nucleus (NucNeoR) would affect antigen presentation. Unexpectedly, NucNeoR was presented at least as efficiently as the cytosolic version of the antigen. Furthermore, presentation of NucNeoR was also dependent on autophagocytosis and lysosomal processing, indicating that both antigens were presented via the same pathway. Inhibition of CRM1-mediated nuclear export did not impede antigen presentation, indicating that NucNeoR gained access to this autophagy-dependent MHC class II presentation pathway by a CRM1-independent route. Thus, this endogenous presentation pathway broadens the spectrum of intracellular antigens surveyed by CD4 + T cells by efficiently sampling cytoplasmic as well as nuclear antigens.

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The Cross‐priming Pathway: A Portrait of an Intricate Immune System

Cited by 59 publications

References 103 publications

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Endogenous presentation of a nuclear antigen on MHC class II by autophagy in the absence of CRM1‐mediated nuclear export

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