Page 298 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 19 Host Defenses in Skin 279

subsequently replenished, under inflammatory conditions by Thus they are able to forgo the canonical MHC class I–antigen
iDCs for the short term and by resident LC-committed stem processing pathway, which requires infection for endogenous
cells that seed the epidermis during fetal development for the expression of the pathogen antigens. Mouse langerin positive
long term. 17,19 dermal DCs are also critical for activating Tfh cells for IgG2a/c
and IgG2b isotype antibody production. In the resting state,
Dermal Dendritic Cells all DCs are poor stimulators of T cells. Interaction with
Dermal DCs efficiently present antigens that have reached the so-called immature DCs can generate unresponsive antigen-
dermis to T cells. In normal skin, multiple subpopulations of specific T cells, a key mechanism for maintaining immune toler-
19
resident dermal DCs can be detected. In mice, dermal langerin ance, which is needed to prevent the immune system from
positive and negative DCs are found, both of which are devel- attacking self tissues.
opmentally distinct from LCs. In humans, most dermal DCs are
langerin negative; only a small number of langerin-dull dermal T Cells and Immune Responses in Skin
DCs can be detected. Nevertheless, human langerin negative Phases of the Cell-Mediated Immune Response in Skin
dermal DCs share functional characteristics with mouse langerin- The adaptive immune response in skin occurs in two phases: (i)
positive dermal DCs. They are able to cross-present captured sensitization (or immunization phase) by first exposure to antigen
intracellular bacterial or viral antigen from infected skin cell and (ii) elicitation (or effector phase) in response to re-exposure
debris to activate CD8 T cells without being infected themselves. to antigen (Fig. 19.3).

SENSITIZATION PHASE EFFECTOR PHASE

First exposure: Second exposure:
Antigen Antigen

SKIN
Epidermis Effector
CD4 or CD8
Langerhans T cells
cell (LC)
(E-cadherin high) ICAM-1
expression on
Activated keratinocytes
migratory LC Local Ag
(E-cadherin low) Resident presentation
dDC dDC Veiled cell CD4 TRM
Dermis (migratory DC) CD8 Recruit PMNs
dDC dDC MHC hi TRM T cells and
langerin – langerin + CD80+ CD86+ other cells
Afferent lymphatics
Post
Dermal capillary
TCM capillary bed venule
Th17
Mature DC Tc17
(APC)
T cell proliferation
Sensitization phase and emigration Effector phase
Activated T cells CTL Activated T cells
CLA pos Tem - home to dermis Th1 TRM - Become effectors:
TRM CD4 : Th1, Th17 TCM Efferent Th1, CTL, Th17, Tc17
TRM CD8 : CTL, Tc17 lymphatics by local DCs in dermis
CLA neg Tcm - remain in LN CLA neg TCM become CLA pos T cells
TCM CD4 : Th1, Th17 DRAINING LYMPH NODE (LN) by cutaneous DCs in LN
TCM CD8 : CTL, Tc17 –home to dermis
FIG 19.3 Phases for the Development of Immune Responses in Skin. During the sensitization
phase, dendritic cells (DCs) capture pathogens in skin and migrate through afferent lymphatics
to the skin draining lymph nodes (LNs), where they present the antigens to naïve T cells. T cell
differentiation is induced by activated cutaneous DCs, and they develop into resident memory
T (T RM ) cells and central memory T (T CM ) cells representing different lineages (Th1, CTL, Th17,
Tc17), depending on DC programming. Activated T CM that leave the LN and migrate to skin
become skin resident T RM, whereas nonactivated T CM stay in lymph nodes. The effector phase
occurs in response to a second exposure to antigen, which activates DCs, which, in turn, activates
local T RM to become effector cells in situ. Activated cutaneous DCs that reach the draining LN
activate T CM to become skin-homing T effector cells that are recruited to the inflamed dermal
site. T effector cells, in concert with recruited cells, will enter into the epidermal layer by binding
intercellular adhesion molecule 1 (ICAM-1) molecules present on activated keratinocytes, to clear
infection, eliminate pathogen-infected cells, remove debris, and repair the skin barrier.