Thus, transport of peptide — MHC II complexes by DCs not only accomplishes transfer from late endocytic compartments to the plasma membrane, but does so in a manner that selectively concentrates TCR ligands and
costimulatory molecules for T cell contact.
After arrival at the cell surface, the MHC and
costimulatory molecules remain clustered.
Formation of
the costimulatory axis was already known to be important for a full immune response, but the present findings propel this axis to the foreground as a key bottleneck.
Insight into this mechanism led the researchers to design new peptides — snippets of the human B7 - 2 receptor protein — that powerfully block the binding of a superantigen to
its costimulatory receptor targets, and thereby protect against lethal toxic shock, as they showed in animals.
Newly - discovered mechanism of action of the bacterial superantigen toxins: Superantigens bind to both B7 - 2 and CD28, the major
costimulatory receptors expressed on human immune cells.
To do so, Olthoff and her colleagues engineered a virus to make a protein called CTLA4Ig, which blocks
the costimulatory signal.
Because previous work in rats and monkeys has found that proteins that block
the costimulatory signal can hold T cells at bay, Kim Olthoff, a transplant surgeon at the University of Pennsylvania Medical Center in Philadelphia, thought her team could achieve a targeted immune suppression by getting the transplanted organ itself — rather than proteins injected into the bloodstream — to block
the costimulatory signal.
But before immune - system fighters called T cells will attack foreign tissue, they must first get a confirmation order of sorts:
a costimulatory signal.
Single - cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and
costimulatory function that are expressed at higher levels in the TEMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4 - CTLs, compared with CD4 + T cells in the central memory (TCM) and effector memory (TEM) subsets.
The role of
costimulatory signals in T cell induction was evaluated in mice lacking the interleukin - 2 (IL - 2) gene.
Upregulation of
costimulatory molecules induced by lipopolysaccharide and double - stranded RNA occurs by Trif - dependent and Trif - independent pathways.
Tseng S - Y, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H. B7 - Dc, a new dendritic cell molecule with potent
costimulatory properties for T cells.
B7h, a novel
costimulatory homolog of B7.
Evidence Implicating the Ras Pathway in Multiple CD28
Costimulatory Functions in CD4 + T Cells.
Decreased expression of B7
costimulatory molecules and major histocompatibility complex class - I in human hepatocellular carcinoma.
Costimulatory members of the TNFR family: Keys to Effective T cell immunity.
Sustained survivin expression from OX40
costimulatory signals drives T cell clonal expansion.
Initial studies demonstrated that ligation of 4 - 1BB on T cells could deliver
costimulatory signals resulting in either increased proliferation or enhanced cytokine secretion and also control clonal expansion and differentiation of effector and memory T cells.
Costimulatory B7 - H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.
The response of T cells can be controlled by
costimulatory molecules present on APC that interact with co-receptors present on the T cell.
In 2002, his group was the first to report the design of «second - generation» CARs that, in addition to a binding domain outside of the T cell and a signaling domain inside, included
a costimulatory domain designed to promote cell proliferation and survival.
When TLRs are triggered by lipopolysaccharides, oral Langerhans cells upregulate expression of coinhibitory molecules B7 - H1 and B7 - H3, whereas expression of
the costimulatory molecule CD86 (B7 - 2) is decreased.
These include T - cell depletion by apoptosis; anergy (ie, the process by which T cells that are presented with a peptide in the absence of
costimulatory signals become refractory to further stimulation with the antigen and are therefore inactivated); and the development of regulatory T cells, which can actively suppress antigen - specific responses following re-challenge with the antigen.
Costimulatory molecule B7 - H1 in primary and metastatic clear cell renal cell carcinoma.
Costimulatory and coinhibitory pathways together with metabolic pathways orchestrate the fate of lymphocytes after antigenic stimulation.
Functionally, T cells stimulated by antigen but without
costimulatory signals, are able to proliferate and expand in numbers, but only transiently, with proliferation being very short - lived and few T cells being able to survive over time (Rogers, 1998, J Immunol).
Dr. Freeman's laboratory focuses on the identification and function of T cell
costimulatory and coinhibitory pathways in regulating T cell activation and application of this knowledge to the development of more effective immunotherapies for cancer, infections, asthma, and autoimmune diseases.
Dr. Sharpe's functional analysis of
costimulatory pathways regulating T cell activation has led to understanding of (1) the roles of B7 - 1 and B7 - 2 as positive regulators through CD28 and (2) negative regulators through CTLA - 4, and (3) the role of PD - L1 and PD - L2 as negative regulators through PD - 1.
We are currently investigating the role of various T - cell
costimulatory pathways in regulating the humoral and cellular responses to and between DENV and ZIKV, and are defining the particular pathways that should be targeted to maximize safety and efficacy of vaccines.
CpG stimulation of precursor B lineage acute lymphoblastic leukemia induces a distinct change in
costimulatory molecule expression and shifts allogeneic T cells towards a Th1 response.
Involved in
the costimulatory signal essential for T - cell receptor (TCR)- mediated T - cell activation.