Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 117

Table 3.20. Proteins in immunological synapse function (Source: [ 221 ]). The microtubule-
organizing center (MTOC) reorients with minus- and plus-ends directed inward and outward,
respectively. Formin-like-1 (FmnL1) and diaphanous-1 (Dia1) are recruited to the immunological
synapse to participate in MTOC polarization. Formins stabilize microtubules at the plasma
membrane and induce formation of actin bundles. Diaphanous-1 associates with IQ motif-
containing GTPase-activating protein (IQGAP) that binds to microtubule tips and links them
to cortical actin. Agent IQGAP also connects to CDC42 and Rac. Microtubule nanomotor
dynein interacts with cytoskeletal adhesion and degranulation-promoting adaptor protein (ADAP).
The ADAP-dynein complex associates with lymphocyte cytosolic protein (LCP; or adaptor
SLP76) and is recruited to the immunological synapse. After MTOC polarization, cytokines and
cytolytic agents are secreted into the immunological synapse within minutes of T-cell receptor
stimulation. Perforin and granzyme are carried into lytic granules (secretory lysosomes) attached
to microtubules. Between-cell communication is achieved via T-cell receptors (TCR). Unlike
cytolytic factors, cytokines (interleukin-2 and -10 and interferon- ) are newly produced after

TCR stimulation and released through the immunological synapse with a time scale of hours. On
the other hand, inflammatory tumor-necrosis factor is transported away from the immunological
synapse (multidirectional path) and forms transmembrane trimers that are released from the plasma
membrane by metallopeptidases. Chemokines, such as CCL3 and CCL5, are also secreted using
the multidirectional path rather than synaptic route. Vesicular transport and membrane fusion
are mediated by soluble N ethylmaleimide-sensitive factor accessory protein receptors vSNARE
and tSNARE, SNARE-binding protein Unc13d, Adaptor protein AP3, and Rab GTPase. Efficient
degranulation requires calcium-regulated proteins such as paxillin that is phosphorylated by ERK
kinase to transit into the immunological synapse. Wiskott-Aldrich syndrome protein (WASP) and
SNARE proteins SNAP23 and syntaxin-11 participate in cytokine release. Effectors of TCRs, such
as kinases

γ

ζ

-associated protein ZAP70, leukocyte-specific non-receptor Tyr kinase (LCK), and
Fyn, adaptors Linker of activated T lymphocytes (LAT) and LCP, and guanine nucleotide-exchange
factor Vav are required in MTOC polarization and molecular secretion, hence thymic development
of T cells.
Process Agents

MTOC polarization ADAP, CDC42, Dia1, dynein, ERK, FmnL1, HDAC6,

IQGAP, PYK2, Rac

Lytic granule release AP3, Munc13-4, paxillin, PKC δ , Rab27a,

SLP1/2, syntaxin-11, WIP

Cytokine secretion Rab3d/19, SNAP23, syntaxin-4/6, WASP

All LAT, LCP, PLC γ ,Src,Vav,ZAP70

3.10.4 T-Lymphocyte Subpopulations

Among the several types of functionally distinct T-cell subsets produced in the thy-
mus, 2 fundamentally different T-cell lineages exist (Table 3.21 ): (1) conventional
αβ T-cell lineages that are generated from common

thymocyte progenitor cells [ 223 ]. Stronger TCR-mediated signals promote

and (2) unconventional γδ

γδ T-cell

lineage development. 111

In addition to TCR signaling, T-cell specification toward

111 Inhibitor of DNA-binding protein ID3 activated by strong TCR signals downstream from the
extracellular signal-regulated kinase and early growth response axis polarizes toward the

γδ

T-cell

γδ αβ

lineage [ 223 ]. Protein ID3 favors the development of T cells and limits that of T cells.