DOCK family proteins: key players in immune surveillance mechanisms.
The DOCK (dedicator of cytokinesis) family of proteins is a group of evolutionary conserved guanine nucleotide exchange factors that play critical roles in cellular processes such as cell migration, adhesion, and cytoskeletal dynamics.
DOCK proteins lead to the reorganization of the actin cytoskeleton and regulation of various cellular functions.
There are several members of the DOCK family, including DOCK1 (DOCK180), DOCK2, DOCK3, and DOCK4, among others.
Each member has its own tissue expression pattern and specific biological functions.
DOCK1 is primarily involved in cell migration, DOCK2 is crucial for lymphocyte migration and immune cell activation, while DOCK3 and DOCK4 have been implicated in neuronal development and synaptogenesis.
The dysregulation of DOCK family proteins can contribute to pathological conditions, including cancer metastasis, immune disorders, and neurological diseases.
The identification of DOCK2 and DOCK8 as causative genes for severe combined immunodeficiency syndromes.
T cells undergo differentiation, proliferation or death through the interaction of the T-cell antigen-receptor (TCR) with antigenic peptide bound to major histocompatibility complex (MHC).
The DOCK family consists of 11 members.
They are classified into four subfamilies—DOCK-A (DOCK1, 2 and 5), DOCK-B (DOCK3 and 4), DOCK-C (DOCK6, 7 and 8) and DOCK-D (DOCK9, 10 and 11)—based on their sequence and substrate specificity.
DOCK2 expression is restricted to hematopoietic cells.
DOCK2 acts downstream of antigen-receptors and chemokine receptors (GPCRs) to control migration, activation and effector functions of leukocytes.
The trafficking of lymphocytes is important for induction of adaptive immune responses: T and B cells migrate into the secondary lymphoid organs (SLOs), such as peripheral lymph nodes (PLNs), spleen and Peyer’s patches, via the blood.
The trafficking of lymphocytes process is regulated by homeostatic chemokines CXCL13, CCL19 and CCL21.
DOCK2 plays key roles in all steps of lymphocyte trafficking.
Engagement of antigen-receptors induces the formation of immunological synapses at the interface between lymphocytes and antigen-bearing cells or target cells.
DOCK2 are involved in neutrophil chemotaxis and production of reactive oxygen species.
Dendritic cells (DCs) are classified into two populations—myeloid DCs (mDCs) and plasmacytoid DCs (pDCs)—according to their morphology, cell surface markers and their functions.
DOCK2 deficiency impaired chemokine-induced activation and migratory responses of pDCs, but not mDCs.
Unlike pDCs, mDCs express DOCK1, DOCK2 and DOCK5.
Bi-allelic DOCK2 mutations cause severe combined immunodeficiency with early-onset, invasive bacterial and viral infections.
Leukocytes from DOCK2-deficient patients exhibit multiple defects: including those in chemotactic responses of T and B cells, degranulation of NK cells, ROS production by neutrophils and type I IFN production by peripheral blood mononuclear cells.
Cholesterol sulfate (CS) is a potent inhibitor of DOCK2.
DOCK8 is expressed in hematopoietic cells, and in non-immune tissues such as lung, pancreas, kidney and placenta.
The bi-allelic DOCK8 mutations cause combined immunodeficiency characterized by recurrent viral infections, early-onset malignancy and atopic dermatitis (AD).
DOCK8 deficiency is rare.
Patients with DOCK8 mutations have morphological and functional abnormalities of leukocytes.
DOCK8 regulates immunological synapse formation in B cells and is required for development or survival of memory CD8+ T cells, NKT cells and lymphoid cells.
The mDCs are the most potent antigen-presenting cells that reside in peripheral tissues such as skin.
mDCs phagocytose antigens and migrate via the afferent lymphatic vessels into the draining peripheral lymphnodes to stimulate T cells.
mDCs then switch their behavior to a highly migratory behavior, which is characterized by the acquisition of a polarized morphology and increased expression of the chemokine receptor CCR7.
Inthe absence of DOCK8, mDCs failed to accumulate in the LN parenchyma for T-cell priming.
DOCK8 acts as negative regulator for IL-31 induction in helper T cells
Blockade of IL-31 signals by a specific antibody for IL-31RA alleviates pruritus in patients with AD.
Observations confirm the crucial roles of DOCK2 and DOCK8 in immune surveillance.
DOCK2 is a major Rac activator critical for migration and activation of leukocytes.
Corticosteroids acts as a naturally occurring DOCK2 inhibitor and mediates immune evasion.
Besides the classically known immune-privileged sites, various tissues, including tumors, also create microenvironments that help them evade immune surveillance.
On the other hand,DOCK8 acts mutations in humans cause combined immunodeficiency characterized by recurrent viral infections, early-onset malignancy, and atopic dermatitis.