Page 210 - Clinical Immunology_ Principles and Practice ( PDFDrive )

190 PART ONE Principles of Immune Response

Counterbalanced Costimulatory and Coinhibitory using CTLA4-Ig fusion proteins (abatacept; belatacept) can
significantly ameliorate synovial inflammation in rheumatoid
Signals Determine T-Cell Response Thresholds arthritis and restrain lymphocyte-driven rejection responses in
As stated earlier, productive T-cell stimulation results from a transplanted kidneys, respectively.
composite of TCR cross-linking and costimulatory signals. Another Ig domain-containing costimulatory molecule, ICOS
Non-TCR activating signals are transduced via a functional family is induced on the T-cell surface following combined TCR and
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of T-cell coreceptor proteins termed costimulatory molecules. An CD28 stimulation. ICOS interaction with APC-expressed ICOS-L
additional array of coreceptors termed coinhibitors serve to is required for development of T-follicular helper (Tfh) cells, a
dampen or restrict potential for TCR-induced cellular activation subset of CD4 cells required for germinal center formation and
and balance the stimulation-promoting effects of costimulatory B-cell antibody class switching. In murine models of rheumatoid
molecules. Although functionally divergent, costimulatory and arthritis and multiple sclerosis, ICOS antibody blockade results
coinhibitory molecules share structural features, such as immu- in reduced Tfh and germinal center formation, associated with
noglobulin (Ig)–like extracellular domains. Key costimulatory suppression of autoimmune responses. ICOS deficiency associates
receptors possessing Ig-like domains include CD28 and ICOS with human common variable immune deficiency (CVID)
(inducible costimulator); coinhibitory counterparts include (Chapter 34), further suggesting that ICOS plays an important
CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed role promoting T-cell dependent humoral immunity.
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death 1), and BTLA (B- and T-lymphocyte attenuator). Increased The CTLA4 coinhibitory molecule shares at least two features
understanding of both activation-promoting and activation- with CD28: membership in the Ig domain–containing superfamily;
restraining coreceptors has recently been exploited to substantial and high-affinity binding capacity for APC-expressed ligands
effect in management of human autoimmune and malignant CD80 and CD86. Unlike CD28, CTLA4 expression is inducible
diseases. in conventional CD4 T cells. However, CTLA4 is present con-
The best-characterized T-cell costimulatory molecule is CD28, stitutively on Treg cells. Experimental data support both T
a constitutively expressed homodimeric transmembrane glyco- cell–intrinsic and cell-extrinsic mechanisms by which CTLA4
protein. 18,20 CD28 binds to two ligands expressed on APCs: B7.1 can limit immune responses. Ligation of CTLA4 induces a
(CD80) and B7.2 (CD86). Ligation of CD28 in isolation has biochemical cascade, including the activation of PP2A and SHP-2
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little effect on T-cell activation; however, when CD28 is engaged phosphatases. In conventional T cells, CTLA4 functions to
along with the TCR, many TCR signals are augmented. Indeed, antagonize the TCR “stop signal,” whereby T cells are induced
concomitant CD28 and TCR engagement is required for activation to pause and maintain lengthy physical contact with antigen-
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of naïve T cells. bearing dendritic cells (DCs). Moreover, using a CTLA4-
CD28 ligation engages several signal transduction pathways dependent process, Treg are thought to limit access of conventional
implicated in T-cell activation. CD28 contains no intrinsic T cells to CD80/CD86 by downregulating these ligands on APCs.
enzymatic activity, but tyrosine residues within its cytoplasmic Monoclonal, antagonist anti-CTLA4 antibodies have been
tail become inducibly phosphorylated during T-cell activation. employed in patients with cancer an attempt to release the
These phosphorylated tyrosines recruit several signal-transducing CTLA4-driven “negative checkpoint” on T-cell function thought
molecules possessing SH2 domains, including GRB2 and the to be impairing natural antitumor T-cell responses. A CTLA4
regulatory p85 subunit of PI3K. TCR- and CD28-dependent antagonist was approved by the US Food and Drug Administration
coactivation of PI3K leads to transactivation of the prosurvival (FDA) in 2011; its use has resulted in sometimes dramatic tumor
genes BCL-2 and BCL-XL. Via GRB2 association, CD28 engages regression and durable remissions in patients with advanced
an NF-κB-dependent survival program dependent on PKCθ and metastatic melanoma and other malignancies.
the GEF VAV1. CD28-driven activation of the GTP-binding Like CTLA4, the coinhibitor PD-1 is an Ig domain-containing
protein RAS-related C3 botulinum toxin substrate 1 (RAC1) is surface receptor negative regulator of T-cell activation, likely
crucial for the protein kinase activity of c-JUN N-terminal kinase through attenuation of TCR-driven PI3K and Akt. Ligation of
(JNK), which, in turn, plays an important role in CD28-dependent PD-1 by cognate ligand PDL-1 (also known as B7-H1) results
T-cell cytokine production and apoptosis resistance. in recruitment of phosphatases, such as SHP2, to motifs within
Costimulation with CD28 agonists dramatically augments the PD-1 cytoplasmic tail. Phosphatase-associated PD-1 interacts
TCR-driven IL-2 production, both by increasing transcription with TCR microclusters, resulting in dephosphorylation of apical
of the IL-2 gene and by stabilizing its messenger RNA (mRNA). 21,22 TCR signaling mediators, including ZAP-70 and CD3ζ, thus
Notably, if the TCR is engaged in the absence of CD28 costimula- dampening TCR signal strength. At a cellular level, PD-1 enforces
tion, activation does not occur. Rather, isolated TCR engagement T-cell unresponsiveness by inhibiting TCR-mediated “stop signals”
leads either to T-cell death by apoptosis (Chapter 13) or to a that promote stable, prolonged contact between T cells and APCs.
state of unresponsiveness known as anergy (see below). CD28 Disruption of PD-1 in mice results in autoantibody formation
is required not only for T-cell priming during infection but is and glomerulonephritis. In chronic viral infections, CD8 T cells
also important for protective secondary T-cell responses during display a hyporesponsive “exhausted” phenotype associated with
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microbial challenge. Significant nonredundant roles for CD28 elevated surface expression of PD-1. 26
have also recently been described in the Treg subset of CD4 T Antibody blockade of PD-1/PDL-1 interactions results in
cells. In animals lacking CD28 specifically in Treg, splenomegaly, restoration of effector functions in exhausted T cells, suggesting
lung inflammation, and accumulation of activated CD4 T cells that PD-1 manipulation could benefit patients with viral infec-
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occur. These findings suggest that the survival- and activation- tions. However, the therapeutic potential of PD-1 has been most
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promoting function of CD28 costimulation is important for dramatically realized in the field of tumor immunotherapy. In
balanced homeostasis of Treg and effector CD4 T-cell subsets. many malignancies, both CD4 and CD8 T cells accumulate within
On balance, inhibition of CD28 ligation by CD80/CD86 results the tumor stroma. Tumor-infiltrating lymphocytes (TILs) are
in decreased immune responses. Blockade of CD28 costimulation characterized by high expression of PD-1 and other coinhibitory