Immunology

Topic: Chemokines
 Table of Contents
o Introduction and structure of monomer
o Nomenclature and classifiction
o Glycosaminoglycans, oligomerization and post-
transcriptional changes
o Chemokine receptors and their types
o Functions of chemokines
o Chemokine receptor switching
 Introduction of Chemokines
• Chemotactic chemokines
• Large family of small secreted proteins
• Signal via G protein-linked heptahelical
chemokine receptor
• Specific arrangement of cysteine
residues(sulphide bridges)
• 3-stranded β-sheet, overlying C-terminal α-
helix, short un-structured N-terminus( receptor
activation)
• Chemokines work in synergy(coperate)
Nomenclature of Chemokines
 Classification of Chemokines
• CCL chemokines- 4 highly conserved cysteines (CCL1- CCL28),
10 receptors
• CXCL chemokines- one amino acid between first and second cysteine

residue (CXCL 1-CXCL16), 6 receptors

• CCL chemokines- three amino acids between first and second
cysteine residue (CCL1 binds to CCR1)
• XCL chemokines- lack cysteine residues at first position. A group of
amino acids attached to cysteine residues
 Factors that effect chemokine activity
• Glucosminoglycans (GAGs)
• Oligomerization of chemokine monomers
• Post-transcriptionl modifications
 Glycosaminoglycan’s(GAGs)
• Chemokines need to interact with GAGs on endothelial cells and in the
extracellular matrix in tissues in order to be presented on the
endothelium of blood vessels and to create a concentration gradient
• Hetero polysaccharides
(amino-sugar + uranic acid)

Functions of GAGs
• Influence chemokines receptor interactions
• Increases chemokines half life and adhesion
• Maintaining interstitial chemokines function and gradients
• CCL21 more sticky while CCL19 diffuses more rapidly through tissues
• TSG-6 interfere with chemokine/GAGs interaction
 Oligomerization
• Chemokines are active as monomers (homodimers + heterodimer)
• This Oligomerization is influenced by GAGs (human CXCL4 and
CCL5, for example, can each heterodimerize/ oligomerize with over 20
other chemokines from CC, CXC, and XC subfamilies)
• Oligomerization influences how individuals or mixture of chemokines
combine to control leukocyte response and disrupting this interaction
may have therapeutic potential
 Post-transcriptional modifications
• Citrullination
• Nitrosylation
• Elastase
• Thrombin cleavage
• Plasmin
• Proteases
These changes also modify the chemokines activity
 Functions of Chemokine Receptors
• Development
• Homeostasis
• Immune survillance
• Infection
• Inflammation
• Immunopathology
 Functions of Chemokine Receptors
Development
• Only the CXCL12/CXCR4/ACKR3 node of the chemokine network is
necessary for life (the most ancient chemokine conserved via evolution).
• CXCR5 and CCR7 serve key developmental roles by regulating the
homing of lymphoid tissue inducer cells (function in organogenesis).
• During embryonic life, these cells migrate out of the blood into sites
where secondary lymphoid tissues will form(lymph nodes and Payer’s
patch).
• Chemokines are involved in the implantation of the early conceptus.
• The migration of subsets of cells during embryonic development, and
the overall growth of the embryo.
 Functions of Chemokine Receptors
Homeostasis
• Several chemokine receptors, including CCR4, CCR9, and particularly
CCR7, contribute to T-cell development. This facilitates the generation of
the naive T-cell receptors, and natural regulatory T-cell formation
• Chemokine-driven homeostatic leukocyte trafficking. For example:
 CCR3 controls steady-state eosinophil distribution
 CXCR2 and CXCR4 direct neutrophil egress from, and return to BM
 Monocytes use CCR1 to patrol blood vessel walls and CCR9 regulates
plasmacytoid Dendritic Cell and intraepithelial T-cell abundance in the
small intestine
 The migration of subsets of cells during embryonic development, and
the overall growth of the embryo.
 Functions of Chemokine Receptors
Immune Surveillance
• Leukocyte migration is of critical
immunological importance.
• Chemokines are of central importance in all
these processes (in the flow sheet) driving
leukocytes into and out of blood and
lymphatic vessels, and directing their
interstitial movement and positioning.
• Without chemokine-directed leukocyte
migration, immune tolerance breaks down,
immuno-surveillance fails, and protective
immune responses are compromised.
 Functions of Chemokine Receptors
At the site of Infection:
• Chemokines along with other proteins, peptides, lipids and microbial
products direct leukocytes recruitment into infected tissues.
• Chemokines are highly inducible and produced in large quantities in
response to different infectious stimuli.
• Leukocytes recruited by chemokines early to damaged or infected tissues
can produce other chemokines that contribute to the next wave of
leukocyte homing (cascade).
• Chemokines are produced by many diseased tissues, including those
affected by autoimmunity, allergy, Alzheimer’s disease, chronic
inflammatory disease, cardiovascular disease, and cancer.
 Chemokine Receptor Switching
• Chemokine receptors switching refers to the process by which cells change
the expression of different chemokine receptors on their surface in response
to different cues from the microenvironment.
• This process allows cells to adapt to changing conditions and to migrate to
different tissues or locations in the body.
• The ability of a cell to switch the chemokine receptors it expresses can have
a significant impact on its behavior, including its ability to migrate,
proliferate, and respond to different types of immune cells.
• Examples: Cancer Cell, T helper cell, etc.
 Factors Influence chemokine receptor switching

Factors that can influence chemokine receptor switching include:

• Cellular context: the type of cell and its environment can influence the
expression of different chemokine receptors. For example, T-helper cells will
express different receptors than monocytes.
• Signaling pathways: various signaling pathways, such as the MAPK/ERK
pathway, can influence chemokine receptor switching by regulating the
expression of different receptors.
• Cellular differentiation: as a cell differentiates, it can change the
chemokine receptors it expresses. For example, during T-cell development,
cells will express different receptors as they mature.
 Factors Influence chemokine receptor switching

Factors that can influence chemokine receptor switching include:

• Inflammatory cues: inflammatory cues such as cytokines and chemokines

can influence chemokine receptor switching by regulating the expression of
different receptors.
• Epigenetic modifications: certain epigenetic modifications can influence
the expression of chemokine receptors, such as methylation of the CCR5
promoter which is associated with HIV-1 resistance.
• Gene mutations: certain gene mutations can also influence chemokine
receptor switching, such as the CCR5 delta 32 mutation which is associated
with HIV-1 resistance.
 Mechanism of Chemokine Receptor Switching

Transcriptional regulation:
• This process involves the activation or suppression of genes that control the
expression of chemokine receptors. This can occur through the binding of
transcription factors to specific DNA sequences in the promoter regions of these
genes, resulting in the upregulation or downregulation of receptor expression.
Post-transcriptional regulation:
• This process involves the modification of the chemokine receptors after they have
been synthesized, including changes in the levels of receptor expression and changes
in the activity of the receptors. This can occur through various mechanisms such as
receptor internalization, degradation, and recycling.
 Examples of Chemokine Receptor Switching
T-helper Cells:
• Chemokine receptor switching is the process by which T-helper cells change the expression of
CCR5 and CXCR4 receptors in response to different inflammatory conditions.
• In the early stages of an infection, T-helper cells express CCR5 receptors which bind to the
chemokine RANTES, allowing the cells to migrate to the site of infection.
• However, as the infection progresses, T-helper cells begin to express CXCR4 receptors, which
bind to the chemokine SDF-1, allowing the cells to migrate to lymphoid organs where they can
differentiate into various subsets of T-helper cells.
Cancer Cells:
• Cancer cells change the expression of different chemokine receptors in order to evade the
immune system and to migrate to different parts of the body.
• Cancer cells can change the expression of chemokine receptors to avoid detection by immune
cells, or to migrate to areas of the body where they can establish new tumors.
 Literature Citations

•Hughes, C. E., & Nibbs, R. J. B. (2018). A guide to chemokines and their receptors. The
FEBS journal, 285(16), 2944–2971. https://doi.org/10.1111/febs.14466
•Zlatko Dembic. (2015). Chapter 7 - Cytokines of the Immune System: Chemokines, The
Cytokines of the Immune System, Academic Press, Pages 241-262, ISBN 9780124199989,
https://www.sciencedirect.com/science/article/pii/B9780124199989000079
• Klaus D. Elgert. (September 8, 2009). Immunology: Understanding immune system (2nd
edition). Wiley-Blackwell, ISBN 0470081570
•Imran Siddiqui, Debora Vignali, Marinos Kallikourdis, Alberto Mantovani, Paola
Allavena, Adoptive T-Cell Therapy: Optimizing Chemokine Receptor-Mediated Homing of T-
Cells in Cancer Immunotherapy, Cancer Immunology, 10.1007/978-3-030-50287-4, (251-271),
(2021).