11 - Cellular Components of the Cutaneous Immune System Flashcards
The innate immune system can adapt to repeated challenges
Provides protection against reinfection in a T- and B-cell-independent manner
Trained immunity
Primary cells of the adaptive immune system
T and B cells
Key players of the innate immune system
Dendritic cells and macrophages
Cellular components of the immune system in healthy skin: epidermal layer
Langerhans cells
Resident memory T cells, primarily CD8+
Cellular components of the immune system in healthy skin: upper dermis
CD4+ T cells
Gamma delta T cells
Cellular components of the immune system in healthy skin: in proximity to the dermal-epidermal junction
Innate lymphoid cells
Cellular components of the immune system in healthy skin: in proximity to dermal blood vessels
Mast cells
Cellular components of the immune system in healthy skin: dermis
Dermal dendritic cells
Macrophages
Both have innate and adaptive immune functions
Interstitial lymphoid cells
Innate-like T cells
Innate vs adaptive response: rapid response
Innate response
Innate vs adaptive response: pattern recognition receptors - germ-line encoded
Innate response
Innate vs adaptive response: recognition - initially low affinity receptors
Adaptive response
Innate vs adaptive response: Gene rearrangement and clonal expansion
Adaptive response
Innate vs adaptive response: direct response for host defense - phagocytosis, antimicrobial activity
Innate response
Innate vs adaptive response: response - T and B cells with receptors encoded by fully rearranged genes
Adaptive response
Innate vs adaptive response: memory
Adaptive response
Progenitor T cells mature in the
Thymus
Key lineages of T cells
Alpha beta
Gamma delta
T cells that have completed their primary development in the thymus, and have not encountered their specific antigen
Naive T cells
Once a naive T cell meets its specific antigen, it is able to develop into
Effector T cell
Central memory T cell
Recognize peptide antigens in the binding pocket of MHC class I molecules Differentiate into cytotoxic effector T cells
Naive CD8+ T cells
Recognize peptide antigens in the binding pocket of MHC class II molecules Differentiates into Th1, Th2, Th17, T follicular helper and T regulatory cells
Naive CD4+ T cells
Characterized by the production of the cytokines IL-2, IFN-gamma, and TNF-alpha and expression of the T-box transcription factor T-bet
T helper 1 cells
Main mediators of cell-mediated immunity
T helper 1 cells
Characterized by the production of IL-4, IL-5, and IL-13
T helper 2 cells
Facilitate humoral (antibody) responses and inhibit some cell-mediated immune responses
T helper 2 cells
Critical for inducing the Th2 program
Zinc-finger transcription factor GATA-3
Produces IL-9; coproduces TNF-alpha
Promotes upregulation of IFN-gamma, IL-13, and IL-17
Found primarily among the skin homing (cutaneous leukocyte antigen positive) T-cell population and are present in healthy human skin
T helper 9 cells
Characterized by the production of the cytokines IL-17A, IL-17F, IL-21, IL-22, and recently IL-26
Involved in antigen responses against extracellular pathogens including both bacteria and fungi
T helper 17 cells
Th17 cells depend on _____ for their survival and expansion
IL-23
Th17 cells are regulated by
Transcription factor RORyt
Key players in the pathogenesis of psoriasis
T helper 17 cells
Key role in maintaining tolerance to self-antigents
T regulatory cells
Loss of _____ happens in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked) syndrome
T regulatory cells
Characterized by the expression of the transcription factor FOXP3
T regulatory cells
Genetic cause of IPEX syndrome
FOXP3
Primarily found in B-cell areas of lymph nodes, spleen, and Payer patches
Trigger the formation and maintenance of germinal centers in lymph nodes and spleen through the expression of CD40 ligand and the secretion of IL-21 and IL-4
T follicular helper cells
To gain entry into the skin, T cells need to express the right surface molecules and receptors. This includes the _____, and expression of specific chemokine receptors including _____
Cutaneous lymphocyte antigen
CCR4, CCR10
An inducible carbohydrate modification of P-selecting glycoprotein ligand-1 (PSGL-1), a known surface glycoprotein that is expressed constitutively on all human peripheral blood T-cells
Able to bind E-selectin which is highly expressed on skin endothelial cells
Cutaneous lymphocyte antigen
Binds to the chemokines CCL17 and CCL22
Present on essentially all skin-homing cells
CCR4
Binds to the chemokine CCL27
Only present on a subset of skin-homing T cells
CCR10
Healthy human skin contains about _____ as many T cells as are present in the entire blood volume, or about _____
Twice
20 billion
Of skin-tropic (CLA+) memory T cells, _____% are located in human skin under non-inflamed conditions
98%
Y/N: T cells that reside in noninflammed human skin are insufficient to create an inflammatory pathology in the absence of recirculating lymphocytes
No - sufficient
Nonrecirculating memory T cells that are found in epithelial barrier tissues, including the GI tract, lung, skin, and productive tract
Tissue resident memory T cells
Tissue resident memory cells have been suggested to exist as 2 phenotypically and functionally distinct populations. Both of these populations express _____ and are distinguished by the expression of _____
Tissue resident memory T cell marker CD69
Surface marker CD103
Type of tissue resident memory T cells: Enriched in the epidermis Predominantly CD8+ Tendency for increased effector cytokine production More limited proliferative capacity
CD69+CD103+ tissue resident memory T cells
Type of tissue resident memory T cells:
More frequently encountered in the dermis
Have slightly lower but still potent effector functions when compared with recirculating T cells
CD69+CD103- tissue resident memory T cells
Coexpress both the skin homing receptor CLA and CCR4 and the central memory markers CCR7/L-selectin (CD62L)
Variable expression of L-selectin
Recirculating memory T cells
Type of recirculating memory T cells:
L-selectin negative
Migratory memory T cells
Type of recirculating memory T cells:
L-selectin positive
Higher sensitivity to antigenic stimulation
Less dependent on costimulation compared to naive T cells
Central memory T cells
Central memory T cells produce mainly
IL-2
After central memory T cell proliferation, they differentiate into
Effector T cells
Characterized by rapid effector function
Capable of producing large amounts of effector cytokines including IFN-gamma, IL-4, and IL-17, as well as perforin in the case of CD8+ T cells
Effector T cells
As these cells do not migrate or recirculate, inflammatory lesions caused by these cells tend to be sharply demarcated, with abrupt cut-off from normal skin, a classic feature of skin lesions in diseases such as psoriasis
Tissue resident memory T cells
As these cells are already on-site, they can respond to repeated antigen challenges extremely rapidly, often within hours of exposure - such as that seen in fixed drug eruptions
Tissue resident memory T cells
The biology of the tissue resident memory T cells can help explain differences between types of cutaneous lymphomas, such as mycosis fungoides which is being mediated by _____, and Sezary syndrome which is being mediated by ______
Tissue resident memory T cells
Recirculating central memory T cells
_____ memory T cell-mediated inflammatory diseases tend to worsen over time, with an increasingly rapid onset of inflammation and increasing severity of inflammation with each exposure
Tissue resident
Characterized by antibody production
B cells
B cells emigrate from the
Bone marrow
B-cell activation usually requires help from
T follicular helper cells
Activated B cells differentiate into
Memory B cells or
Antibody-secreting plasma cells
Induces immunoglobulin A responses
TGF-beta
B cells have been observed in
Chronic inflammatory skin conditions such as: Cutaneous leishmaniasis Diffuse cutaneous sclerosis Cutaneous lupus Atopic dermatitis
Plasma cells can be found in
Certain inflammatory conditions such as:
Syphilis
Leprosy
Have been found to have an anti-inflammatory effect
Named B-regulatory cells or Bregs
IL-10 producing B cells
Nonrecirculating lymphocyte populations
Span the continuum between the innate and adaptive immune system and share a number of features pertaining to their tissue-resident functions
Unconventional and innate-like T cells
Innate lymphoid cells
Defined by 3 main features:
Absence of recombinant activating gene (RAG)-dependent rearranged antigen receptors
Lack of myeloid and dendritic cell phenotypical markers (negative lineage markers)
Lymphoid morphology
Innate lymphoid cells
Express the IL-7 receptor alpha chain CD127
Innate lymphoid cells
Innate lymphoid cells require _____ for their development
IL-17
Innate lymphoid cells can be subdivided into
Innate lymphoid cell 1
Innate lymphoid cell 2
Innate lymphoid cell 3
Innate lymphoid cell type:
Similar to Th1 cells, generate IFN-gamma and TNF-alpha, have no cytotoxic molecules, and are dependent on T-bet
ILC1
Innate lymphoid cell type:
Express and produce Th2 cytokines, including IL-4, IL-5, and IL-13, and have a high expression of the GATA-3 transcription factor
ILC2
Innate lymphoid cell type:
Expressing variable levels of the transcription factors ROR gamma t, aryl-hydrocarbon receptor, and T-bet, and release variable amounts of IFN-gamma, IL-22, and IL-17
ILC3
Innate lymphoid cells exhibit a close spatial relationship to
T lymphocytes
Innate lymphoid cells exhibit a close spatial relationship to
T lymphocytes
Express T-cell receptors of limited diversity, which recognize antigens in the context of nonclassical MHC-like molecules, or independent of MHC-related presenting molecules altogether
Expand the repertoire of antigens recognized by T cells
Unconventional or innate-like T cells
Y/N: Unconventional T cells respond more slowly compared with their conventional counterparts
No - more quickly
Lymphocytes belonging to this group: unconventional and innate-like T cells
Invariant natural killer T cells
Mucosal-associated invariant T cells
Gamma delta T cells
Structurally related to MHC class I genes Unlike MHC class I molecules: non-polymorphic
Cluster of differentiation 1 (CD1) gene family
CD1 molecules: The _____ molecules are more closely homologous to one another than to _____
CD1a, b, and c
CD1d
CD1 molecules: The _____ isoforms are present on the surface of Langerhans cells, whereas _____ are expressed on dermal dendritic cells
CD1a and c
CD1a, b, and c
Epidermal dendritic cells that mediate innate immune responses in skin, with phagocytic and antimicrobial function as well as a key role in antigen presentation to T cells
Langerhans cells
Characterized by their high expression of CD1a and unique expression of langerin (CD207)
Langerhans cells
Required for Birbeck granule formation
Langerin
Secrete Th1 cytokines; cytolytic against infected targets as in case of myobacterial infections; trigger antimicrobial activity
Express perforin, granzyme B, and the antimicrobial protein granulysin
CD1-restricted T cells
Cooperates with granulysin in killing intracellular bacteria
Granzyme B
The expression of _____, as has been shown in leprosy, correlates with containment of infection, and is approximately 6-fold more frequent in tuberculous leprosy than lepromatous leprosy skin lesions
Granulysin
Subset of T cells that express an invariant T-cell receptor, paired with TCR beta of limited diversity
Recognize glycolipid antigens presented by the MHC class-I like molecule CD1d
Invariant natural killer cells
Invariant natural killer cells are dependent on _____ for their development
Transcriptional factor PLZF
Five major distinct invariant natural killer cell subsets express and mirror _____ subsets in cytokine prouduction
T helper cell
iNKT1 - Th1
iNKT2 - Th2
iNKT17 - Th17
Subset of T cells that express a semi-variant T cell receptor combining a unique TCR alpha chain
Evolutionarily conserved and have a capacity for rapid effector function
Mucosal-associated invariant T cells
Activated by bacterial riboflavin biosynthesis intermediates that are presented by the MCH class-I like molecule MR1
Mucosal-associated invariant T cells
As mammals do not synthesize riboflavin, but instead rely on certain bacteria and yeast, _____ provide a means to control certain commensal bacteria and assess and control for either overgrowth or infection by these organisms
Mucosal-associated invariant T cells
Characterized by the expression of the gamma delta T cell receptor, and in contrast to the strict MHC restriction of alpha beta T-cells, several modes of antigen-recognization have been described
Have an ability to self-renew in tissues independently of circulating precursors
Gamma delta T cells
While representing the majority of lymphocytes in mouse skin, _____ only represent a small fraction (1% to 2%) of resident T cells in human skin
Gamma delta T cells
Large granular lymphocytes
Characterized by being CD16+ CD56+ CD94+ CD161+ but negative for the T-cell markers CD3
Natural killer cells
Have a role in surveying the body, looking for altered cells, either transformed or infected with viruses or parasites
Natural killer cells
Main function is to process antigen material and present it on the cell surface and activate T cells
Dendritic cells
3 cutaneous dendritic cell populations in healthy skin
Epidermal Langerhans cells
Resident dermal conventional dendritic cells
Plasmacytoid dendritic cells
Previously called myeloid dendritic cells
Conventional dendritic cells
Permits the presentation of exogenous antigens, which are normally presented by MHC class II molecules, to be presented by MHC class I molecules
Cross-presentation
Important for immune defenses against many viruses and in elimination of autoreactive CD8+ T cells
Cross-presentation pathways
The inflammatory dendritic cells in psoriasis produce TNF-alpha
and have inducible nitric oxide synthetase (iNOS) and have been termed
Tip-DCs
Unique population of resident cutaneous dendritic cells, initially described by their morphology, which is similar to plasma cells
Plasmacytoid dendritic cells
Sentinels in early defences against viral infection, particularly given their expression of TLR 7 and TLR9, and intracellular nucleic sensor such as RIG-1, that functions as a pattern recognition receptor for certain single stranded RNA viruses
Produce large amounts of type 1 interferons
Plasmacytoid dendritic cells
Y/N: In contrast to conventional dendritic cells, plasmacytoid dendritic cells express more MCH class II and co-stimulatory molecules on their surface, and the process antigens more efficiently
No - express less MCH class II and co-stimulatory molecules process antigens less efficiently
Langerhans cells account for _____% of cells in the epidermis
2-4
Langerhans cells require the cytokines _____, both derived from keratinoytes, for their development and epidermal residence
IL-34
TGF-beta
Essential component of innate immunity and play a central role in inflammation
Macrophages
Also known as classically activated macrophages
Activated primarily by IFN-gamma
Produce pro-inflammatory cytokines such as IL-1beta, TNF-alpha, IL-12, and IL-18
M1 macrophages
Phagocytize large numbers of pathogens and kill intracellular bacteria
Vitamin D is required for the adaptive immune responses to overcome the ability of intracellular pathogens to avoid this killing
M1 macrophages
Also known as alternatively activating macrophages
Activated primarily by stimuli such as IL-4, IL-10, TGF-beta, and IL-13
M2 macrophages
Central role in response to parasites, tissue remodeling, and allergic diseases, and may have a role in resolution of skin inflammation
M2 macrophages
Central role in response to parasites, tissue remodeling, and allergic diseases, and may have a role in resolution of skin inflammation
M2 macrophages
Usually most abundant at epithelial sites, such as the skin and mucosal tissue, where they are ideally situated to act as a first line of defense
Mast cells
Key factors influencing the maturation of mast cells, including _____, which binds to the c-kit receptor (CD117), and IL-3
Stem cell factor, also known as KIT ligand
Y/N: Mast cells are long-lived cells that can survive in tissues for months to years
Yes
Best known cause of mast cell activation is when
Antigens crosslink IgE bound to receptors for igE
Mast cells can also bind _____ antibodies
IgG
Y/N: A relatively low level of allergen is sufficient to trigger degranulation of mast cells
Yes
Mast cells granules are filled with preformed compounds such as
Histamine
Serotonin
Can also produce a large number of cytokine following activation, including TNF-alpha, IL-3, IL-4, IL-5, and IL-6, as well as lipid mediators such as leukotrienes, prostaglandins, and platelet-activating factor
Mast cells
Given the presence of cytokines such as IL-4, mast cell responses are more directed toward Th_____ responses
2
Classified as granulocytes
Basophils
Neutrophils
Eosinophils
Most abundant leukocytes in the blood accounting for about 45% to 70% of the peripheral blood leukocytes
Neutrophils
Neutrophils are short-lived with a life span somewhere between
5 and 90 hours
Generation of neutrophils is controlled by
Granulocyte colony-stimulating factor
Hallmark cell of acute inflammation
Neutrophil
Y/N: On a per-cell basis, neutrophils make fewer
molecules of a given cytokine than macrophages or lymphocytes, but neutrophils often outnumber other leukocytes at inflammatory sites by several orders of magnitude
Yes
Neutrophil recruitment can be amplified exponentially in a phase termed
Neutrophil swarming
Neutrophil granules:
Include proteins such as lactoferrin, lipocalin, and cathelicidin (LL37) along with several metalloproteinases
Have an important role in facilitating neutrophil recruitment and tissue breakdown
Peroxidase-negative
Neutrophil granules:
Next granules to be emptied usually occurring as the concentration of chemoattractants increases
Peroxidase-positive
Iron-containing enzyme that colors pus green
Myeloperoxidase
The _____ released by neutrophils have been shown to cleave the IL-36 cytokines into their more active forms
Serine proteases
Neutrophil _____ has been shown to cleave the IL-36 receptor antagonist into its highly active antagonistic form
Elastase
Rapid release of reactive oxygen species driven by the NADPH oxidase
Used by neutrophils to degrade bacteria and particles that have been ingested
Respiratory burst
Neutrophils undergo a unique form of cell death in which the nuclear chromatin is released into the extracellular space and forms a matrix known as
Neutrophil extracellular traps
Neutrophil extracellular trap formation requires the generation of ROS, and patients with _____, apart from having defective respiratory burst, also have reduced NET formation
Chronic granulomatous disease
Neutrophil activation can lead to substantial tissue damage, evident from disorders such as
Pyoderma gangrenosum
Neutrophils can leave sites of inflammation in a process termed
Neutrophil reverse migration
Eosinophils have the capacity to be stained by (acidophilic/basophilic) dyes
Acidophilic
Eosinophils are readily recruited into tissues in response to appropriate stimuli such as
IL-5
Eotaxin chemokines CCL11 (eotaxin-1), CCL13, and CCL26 (eotaxin-3)
Eosinophils account for somewhere between _____% of peripheral blood leukocytes
0 and 5
The granules in eosinophils contain 4 major proteins
Eosinophilic peroxidase
Major basic protein
Ribonucleases eosinophilic cationic protein
Eosinophil-derived neurotoxin
When eosinophils are in tissues, they are usually found in proximity to
Mast cells
Least common type of granulocyte
Basophil
Basophils account for less than _____% of peripheral blood leukocytes
1
Basophils were for a long time thought to be a redundant variant of _____ in the blood
Mast cells
In contrast to mast cells, which mature in _____, basophils complete their maturation in _____
Tissues
Bone marrow
Basophils have a life span of _____, in contrast to _____ for mast cells
Several days
Weeks to years
Y/N: Basophils retain the ability to proliferate unlike mast cells
No - Do not retain
Basophils are an important source of _____ cytokines, and secrete large quantities of _____, suggesting that basophils may be involved in mediating allergic diseases and immunity against parasites
Th2-type
IL-4
Most abundant cell type in skin and form the epidermis
Keratinocytes
(High/Low) pH of the skin inhibits growth of bacteria
Low
Another term used for keratinocytes because of the production of antimicrobial peptides, cytokines, and chemokines
Cytokinocyte
