52,426 research outputs found
Antigen depot is not required for alum adjuvanticity
Alum adjuvants have been in continuous clinical use for more than 80 yr. While the prevailing theory has been that depot formation and the associated slow release of antigen and/or inflammation are responsible for alum enhancement of antigen presentation and subsequent T- and B-cell responses, this has never been formally proven. To examine antigen persistence, we used the chimeric fluorescent protein EαGFP, which allows assessment of antigen presentation in situ, using the Y-Ae antibody. We demonstrate that alum and/or CpG adjuvants induced similar uptake of antigen, and in all cases, GFP signal did not persist beyond 24 h in draining lymph node antigen-presenting cells. Antigen presentation was first detectable on B cells within 6â12 h of antigen administration, followed by conventional dendritic cells (DCs) at 12â24 h, then finally plasmacytoid DCs at 48 h or later. Again, alum and/or CpG adjuvants did not have an effect on the magnitude or sequence of this response; furthermore, they induced similar antigen-specific T-cell activation in vivo. Notably, removal of the injection site and associated alum depot, as early as 2 h after administration, had no appreciable effect on antigen-specific T- and B-cell responses. This study clearly rules out a role for depot formation in alum adjuvant activity
Regulation of T cell expansion by antigen presentation dynamics
An essential feature of the adaptive immune system is the proliferation of
antigen-specific lymphocytes during an immune reaction to form a large pool of
effector cells. This proliferation must be regulated to ensure an effective
response to infection while avoiding immunopathology. Recent experiments in
mice have demonstrated that the expansion of a specific clone of T cells in
response to cognate antigen obeys a striking inverse power law with respect to
the initial number of T cells. Here, we show that such a relationship arises
naturally from a model in which T cell expansion is limited by decaying levels
of presented antigen. The same model also accounts for the observed dependence
of T cell expansion on affinity for antigen and on the kinetics of antigen
administration. Extending the model to address expansion of multiple T cell
clones competing for antigen, we find that higher affinity clones can suppress
the proliferation of lower affinity clones, thereby promoting the specificity
of the response. Employing the model to derive optimal vaccination protocols,
we find that exponentially increasing antigen doses can achieve a nearly
optimized response. We thus conclude that the dynamics of presented antigen is
a key regulator of both the size and specificity of the adaptive immune
response
Antigen-presenting cells and antigen presentation in tertiary lymphoid organs
Tertiary lymphoid organs (TLOs) form in territorialized niches of peripheral tissues characterized by the presence of antigens; however, little is known about mechanism(s) of antigen handling by ectopic lymphoid structures. In this mini review, we will discuss the role of antigen-presenting cells and mechanisms of antigen presentation in TLOs, summarizing what is currently known about this facet of the formation and function of these tissues as well as identifying questions yet to be addressed
Biomimetic polyelectrolyte microparticles facilitate antigen presentation by porcine dendritic cells
Short-term antigen presentation and single clonal burst limit the magnitude of the CD8(+) T cell responses to malaria liver stages.
Malaria sporozoites induce swift activation of antigen-specific CD8(+) T cells that inhibit the intracellular development of liver-stage parasites. The length of time of functional in vivo antigen presentation, estimated by monitoring the activation of antigen-specific CD8(+) T cells, is of short duration, with maximum T cell activation occurring within the first 8 h after immunization and lasting approximately 48 h. Although the magnitude of the CD8(+) T cell response closely correlates with the number of parasites used for immunization, increasing the time of antigen presentation by daily immunizations does not enhance the magnitude of this response. Thus, once a primary clonal burst is established, the CD8(+) T cell response becomes refractory or unresponsive to further antigenic stimulation. These findings strongly suggest that the most efficient strategy for the induction of primary CD8(+) T cell responses is the delivery of a maximal amount of antigen in a single dose, thereby ensuring a clonal burst that involves the largest number of precursors to become memory cells
A role for the Hsp90 molecular chaperone family in antigen presentation to T lymphocytes via major histocompatibility complex class II molecules
The heat shock protein (HSP) Hsp90 is known to chaperone cytosolic peptides for MHC class I (MHCI)-restricted antigen presentation to T lymphocytes. We now demonstrate a role for Hsp90 activity in presentation of antigens on MHCII. Treatment of mouse antigen-presenting cells (APC) with the pharmacological Hsp90 inhibitor, geldanamycin, inhibited MHCII-mediated presentation of endocytosed and cytosolic proteins as well as synthetic peptides to specific T cells. Ectopic expression of human Hsp90 in APC enhanced MHCII-mediated antigen presentation. Further, pharmacological Hsp90 inhibition reduced, while retroviral Hsp90 overexpression enhanced, the levels of stable compact MHCII heterodimers correlating with the antigen presentation phenotype. Pharmacological inhibition of Hsp90 activity in IFN-Îł-treated APC resulted in severe abrogation of MHCII-restricted presentation of cytosolic antigen, but only partially inhibited exogenous antigen presentation. Our data suggest a major role for Hsp90 activity in MHCII-mediated antigen presentation pathways, and implicate IFN-Îł-inducible Hsp90-independent mechanisms
PEPTIDE VACCINE FORMULATION CONTROLS THE DURATION OF ANTIGEN PRESENTATION AND MAGNITUDE OF TUMORâSPECIFIC CD8+ T CELL RESPONSE
Despite remarkable progresses in vaccinology, therapeutic cancer vaccines have not achieved their full potential. We previously showed that the duration of antigen presentation critically affected the quantity and quality of T cell response and subsequent antiâtumor efficacy. Here we describe Lâtyrosine amino acidâbased microparticles as a novel peptide vaccine adjuvant for the induction of tumorâspecific T cells. Lâtyrosine microparticles did not induce inflammasome activation, but instead extended antigen presentation time. The consequent prolongation in antigen presentation translated into prolonged T cell proliferation and superior numbers and antiâtumor function of vaccinationâinduced CD8+ T cells. Indeed, prolonging antigen presentation by repeated injection of peptide in saline resulted in an increase in T cell numbers similar to that observed after vaccination with peptide/Lâtyrosine microparticles. These results suggest that the duration of antigen presentation is critical for optimal induction of antiâtumor T cells, and can be manipulated through proper vaccine formulation
Antigen presentation to B cells
B cells are capable of mounting responses to a bewildering range of potentially pathogenic antigens through the production of high-affinity antibodies and the establishment of immunological memory. Thus, regulated B-cell activation is critical for protection against a variety of bacterial and viral infections, as well as cancers. Here, we discuss a number of recent imaging studies that have provided new insights into the variety of mechanisms by which B-cell activation is initiated in the lymph node in vivo
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