In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance

Zinselmeyer, Bernd H.; Dempster, John; Gurney, Alison M.; Wokosin, David L.; Miller, Mark J.; Ho, Hsiang‐Ling; Millington, Owain R.; Smith, Karen; Rush, Catherine M.; Parker, Ian; Cahalan, Michael D.; Brewer, James M.; Garside, Paul

doi:10.1084/jem.20050203

Cited by 140 publications

(148 citation statements)

References 32 publications

(113 reference statements)

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“…Time points between stacks ranged from 18 to 48 s depending on the settings for each experiment. Multi-dimensional rendering was performed with Imaris (Bitplane) and cell tracking was performed with PicViewer Software (John Dempster University of Strathclyde) [16].…”

Section: Methodsmentioning

confidence: 99%

Video-rate two-photon imaging of mouse footpad – a promising model for studying leukocyte recruitment dynamics during inflammation

et al. 2008

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Leukocyte recruitment is a key host defense mechanism to infection and a salient feature of autoimmune diseases such as arthritis. The cell dynamics of these processes are difficult to study due to the challenge of tracking cells flowing in the circulation and migrating through light scattering tissues. Here, we describe a noninvasive two-photon (2P) microscopy approach to study leukocyte homing in the mouse footpad. In the absence of inflammation, cells moved > several hundred m/s in vessels and only rarely adhered to endothelium or entered the tissue parenchyma. In response to bacterial infection, neutrophils moved in small capillaries at reduced speeds of (14-45 m/min) and rolled in larger vessels at 5-60 m/min. Within minutes of adoptive transfer, neutrophils entered the connective tissue and crawled with a median velocity of 7.3 m/min. 2P imaging has excellent spatiotemporal resolution and is a promising in vivo approach to study the cellular basis of inflammation.

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Section: Methodsmentioning

confidence: 99%

Video-rate two-photon imaging of mouse footpad – a promising model for studying leukocyte recruitment dynamics during inflammation

et al. 2008

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“…However, in a growing fraction of the industrialized world, contact, ingestion, or inhalation of such allergens provokes harmful and sometimes fatal allergic responses (1,2). It appears that the nature of the Ag, the specific tissue microenvironment at the site of initial encounter, and molecular events in the draining lymph node (LN) 3 are critical in establishing whether long-lived immunity or tolerance prevails (3)(4)(5)(6)(7)(8).…”

Section: Inhalation Tolerance Is Induced Selectively In Thoracic Lymphmentioning

confidence: 99%

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

Álvarez

Świrski

Yang

et al. 2006

The Journal of Immunology

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Under immunogenic conditions, both the site of initial Ag exposure and consequent T cell priming in specific draining lymph nodes (LNs) imprint the ensuing immune response with lasting tissue-selective tropism. With respect to immune tolerance, whether the site of tolerance induction leads to compartmentalized or, alternatively, pervasive tolerance has not been formally investigated. Using a murine model of inhalation tolerance, we investigated whether the induction of respiratory mucosal tolerance precludes the development of de novo Th2 sensitization upon subsequent exposure to the same Ag at distant mucosal (gut) and nonmucosal (cutaneous) sites. By tracking the proliferation of CFSE-labeled OVA-TCR transgenic CD4+ T cells upon OVA inhalation in vivo, we defined the site of tolerance induction to be restricted to the thoracic LNs. Expectedly, inhalation tolerance prevented de novo Th2 sensitization upon subsequent exposure to the same Ag at the same site. Importantly, although gut- and skin-draining LNs were not used during tolerance induction, de novo Ag-specific proliferation and Th2 differentiation in these LNs, as well as memory/effector Th2 responses in the gut (allergic diarrhea) and skin (late-phase cutaneous responses) were inhibited upon immunogenic challenge to the same Ag. Interestingly, this pervasive tolerogenic phenotype was not associated with the presence of suppressive activity throughout the lymphatics; indeed, potent suppressive activity was detected solely in the spleen. These data indicate that while inhalation tolerance is selectively induced in local thoracic LNs, its tolerogenic activity resides systemically and leads to pervasive immune tolerance in distant mucosal and nonmucosal sites.

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“…The decision for a T cell to ''stop'' and form long-lived contacts with a DC when scanning for cognate antigen may depend on multiple parameters, but antigen density (12) and peptide affinity for class II (19) have been shown to augment the frequency of prolonged DC:T cell contacts, increasing the efficiency of the T cell stop signal. Recent studies have also suggested the requirement of stable DC:T cell interactions for the induction of immunity, rather than tolerance (15,(20)(21)(22). Strikingly, recent publications suggest that peptide:class II complexes that persist for long periods of time may be an essential feature of a germinal center reaction (23,24).…”

mentioning

confidence: 99%

“…However, it is unknown whether these low-stability peptide:class II complexes are otherwise competent to recruit CD4 T cells if intracellular antigen processing is bypassed. The need for extended interactions of antigen-bearing APC by CD4 T cells (15,(20)(21)(22) suggests that persistence of cell surface complexes may be a generalized feature of the ability of a peptide to recruit T cells. To explore this issue, we evaluated whether CD4 T cell responses to low-stability peptide:class II complexes can be sustained over time.…”

mentioning

confidence: 99%

“…CD4 T cell expansion is then evaluated by assessing the number of responding T cells at the peak of the immune response via IL-2 ELISpot assays. All peptides were emulsified in IFA containing LPS as an adjuvant.Initial studies used the well-defined, cryptic peptide HEL [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], which has very unstable interactions with I-A d (t 1/2 12 h). When…”

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confidence: 99%

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Abortive activation of CD4 T cell responses during competitive priming in vivo

Weaver

Chaves

Sant

2009

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

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Immunodominance refers to the highly selective peptide reactivity of T cells during an immune response. In this study, we tested the hypothesis that persistence of peptide:class II complexes is one key parameter that selects the final specificity of CD4 T cells. We found that low-stability peptide:class II complexes support the initial priming and expansion of CD4 T cells, but the expansion becomes strikingly aborted in the presence of competitive T cell responses to unrelated peptides. Our experiments revealed that for inhibition to occur, the competitive responses must be initiated by the same antigen presenting cell, and it is not because of competition for MHC binding. These studies not only provide an insight into the events that regulate competitive CD4 T cell priming in vivo, but also provide a previously undescribed conceptual framework to understand the parameters that select the final specificity of the T cell repertoire during pathogen or vaccine-induced immune responses.A ntigen presenting cells (APC) ingest antigens in peripheral tissues and, in response to inflammatory signals, migrate to lymph nodes (LNs), where they present peptide antigens bound to MHC class II molecules to recirculating CD4 T cells. The majority of T cells that are primed during an immune response are selectively skewed to one or a few of the many possible peptides from an antigen, resulting in a phenomenon known as immunodominance. Our laboratory has shown that an intrinsic biochemical property of the ligand recognized by the responding T cells, the kinetic stability of the peptide:MHC class II complexes, has the major role in both predicting and determining immunodominance (1). High-stability peptides elicit dominant responses, whereas low-stability peptides do not recruit detectable responses and are thus, ''cryptic'' (1). Selectivity in the repertoire of the presented peptide:class II complexes was shown to be modulated by DM editing in APC (2-4), and to be independent of the protein context in which those peptides resided (5).Recent findings describing the dynamic interactions of antigenbearing dendritic cells (DC) and T cells suggest that peptide off-rates from class II molecules may impact the immune response (6-8). The quality of signals received through the T cell antigen receptor (TcR) by peptides of different affinity for MHC class II has recently been suggested to regulate the fate and function of CD4 T cells (9, 10). Despite new methods that allow visualization of different phases of DC:T cell interactions to antigenic stimulus in vivo (11-18), the factors that contribute to efficient T cell activation and how the kinetic features of those interactions governs the fate of the responding T cells is still unknown. The decision for a T cell to ''stop'' and form long-lived contacts with a DC when scanning for cognate antigen may depend on multiple parameters, but antigen density (12) and peptide affinity for class II (19) have been shown to augment the frequency of prolonged DC:T cell contacts, increasing the efficienc...

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In situ characterization of CD4+ T cell behavior in mucosal and systemic lymphoid tissues during the induction of oral priming and tolerance

Cited by 140 publications

References 32 publications

Video-rate two-photon imaging of mouse footpad – a promising model for studying leukocyte recruitment dynamics during inflammation

Video-rate two-photon imaging of mouse footpad – a promising model for studying leukocyte recruitment dynamics during inflammation

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

Abortive activation of CD4 T cell responses during competitive priming in vivo

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