T Lymphocytes in Cutaneous Immunity
Introduction
T lymphocytes are the central orchestrators of adaptive immunity, providing antigen-specific responses, long-term memory, and the ability to discriminate self from non-self. skin contains an enormous population of T cells—estimated at 20 billion in human skin, twice the number in blood—reflecting the skin's importance as an immunological organ.
Understanding T cell subsets, their differentiation, and their pathologic roles is essential for dermatologists because T cells drive numerous skin diseases from psoriasis (Th17) to atopic dermatitis (Th2) to vitiligo (CD8+ cytotoxic T cells).
T Cell Development and Antigen Recognition
T Cell Receptor (TCR) Structure
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MHC Restriction
| TCR Type | Coreceptor | Recognizes | Target Cell |
|---|
| αβ TCR + CD4 | CD4 | MHC II + peptide | APCs (DCs, macrophages, B cells) |
| αβ TCR + CD8 | CD8 | MHC I + peptide | All nucleated cells |
| γδ TCR | Usually neither | Non-classical MHC, lipids | Epithelial cells |
CD4+ T Helper Subsets
T Helper Differentiation Paradigm
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Th1 Cells
| Feature | Details |
|---|
| Master regulator | T-bet |
| Inducing cytokines | IL-12 (DCs), IFN-γ |
| Signature cytokines | IFN-γ, TNF-α, IL-2 |
| Function | Macrophage activation, intracellular pathogen clearance |
| Skin diseases | Contact dermatitis, tuberculoid leprosy, sarcoidosis |
Th2 Cells
| Feature | Details |
|---|
| Master regulator | GATA3 |
| Inducing cytokines | IL-4 (basophils, mast cells, ILC2) |
| Signature cytokines | IL-4, IL-5, IL-13, IL-31 |
| Function | Helminth defense, IgE class switching, barrier disruption |
| Skin diseases | Atopic dermatitis, urticaria, drug eruptions |
Th17 Cells
| Feature | Details |
|---|
| Master regulator | RORγt |
| Inducing cytokines | IL-6, IL-23, TGF-β, IL-1β |
| Signature cytokines | IL-17A, IL-17F, IL-22, IL-26 |
| Function | Neutrophil recruitment, AMP induction, extracellular pathogen defense |
| Skin diseases | Psoriasis (central), hidradenitis suppurativa |
Th22 Cells
| Feature | Details |
|---|
| Master regulator | Not clearly defined (AHR involved) |
| Signature cytokine | IL-22 (without IL-17) |
| Function | Epithelial proliferation, AMP production, barrier repair |
| Skin diseases | Psoriasis, wound healing |
Regulatory T Cells (Tregs)
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Skin-Resident Tregs
Skin contains a specialized population of Foxp3+ Tregs:
| Feature | Details |
|---|
| Location | Hair follicle-associated |
| Function | Tolerance to commensals, hair follicle cycling |
| Hair role | Facilitate hair follicle stem cell function |
| Disease relevance | Deficiency → alopecia areata, vitiligo |
CD8+ Cytotoxic T Lymphocytes (CTLs)
CTL Mechanism of Killing
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CTLs in Skin Disease
| Disease | CTL Target | Mechanism |
|---|
| Vitiligo | Melanocytes | Melanocyte-specific CTLs destroy pigment cells |
| Lichenoid dermatoses | Keratinocytes | Basal layer apoptosis (civatte bodies) |
| Stevens-Johnson syndrome/TEN | Keratinocytes | Massive epidermal necrosis |
| Graft-versus-host disease | Keratinocytes | Donor CTLs attack host epidermis |
| Drug reactions | Multiple | HLA-restricted drug hypersensitivity |
Tissue-Resident Memory T Cells (TRM)
TRM Revolution
TRM cells represent a paradigm shift in understanding adaptive immunity—most memory T cells don't circulate but reside permanently in tissues.
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TRM in Skin Diseases
| Disease | TRM Role | Clinical Implication |
|---|
| Recurrent HSV | HSV-specific CD8+ TRM at ganglia/skin | Rapid containment, site-specific recurrence |
| Psoriasis | IL-17+ TRM in resolved lesions | Explains recurrence at same sites |
| Vitiligo | Melanocyte-specific TRM | Target for JAK inhibitors |
| Fixed drug eruption | Drug-specific TRM at fixed sites | Site specificity explained |
| Alopecia areata | CD8+ TRM around hair bulb | Target for emerging therapies |
γδ T Cells
Unique Features of γδ T Cells
| Feature | αβ T Cells | γδ T Cells |
|---|
| TCR chains | α + β | γ + δ |
| MHC restriction | MHC I or II | Often MHC-independent |
| Antigen | Peptides | Phosphoantigens, lipids, stress ligands |
| Distribution | Blood, tissues | Epithelia (including skin) |
| Development | Thymus | Thymus, may mature extrathymically |
Dendritic Epidermal T Cells (DETCs)
In mice, the epidermis contains a population of γδ T cells (DETCs) with important functions in wound healing and stress surveillance. Human skin has fewer epidermal γδ T cells but does contain dermal γδ T cells:
| Function | Mechanism |
|---|
| Wound healing | IGF-1, KGF production |
| Tumor surveillance | NKG2D-mediated killing |
| Stress response | Recognition of stressed keratinocytes |
T Cell Trafficking to Skin
Skin-Homing Receptors
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Imprinting Skin Tropism
T cells acquire skin-homing capacity when primed by skin-derived DCs in the presence of vitamin D and vitamin A metabolites:
| Factor | Source | Effect |
|---|
| 1,25(OH)₂D₃ | UV-exposed keratinocytes | ↑ CCR10 (skin tropism) |
| Retinoic acid | LN stromal cells | Generally ↑ gut tropism |
| Skin DC priming | Langerhans cells, dDCs | CLA expression |
T Cells in Specific Skin Diseases
Psoriasis: Th17 Disease
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Atopic Dermatitis: Th2 and Beyond
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Summary: T Cell Subsets in Skin Disease
| Disease | Dominant T Cells | Key Cytokines | Therapeutic Target |
|---|
| Psoriasis | Th17, Tc17, γδ17 | IL-17, IL-22, IL-23 | IL-23, IL-17 |
| Atopic dermatitis | Th2 (acute), Th22 | IL-4, IL-13, IL-31 | IL-4Rα, IL-31, JAK |
| Vitiligo | CD8+ CTL | IFN-γ, TNF | JAK (blocks IFN-γ) |
| Alopecia areata | CD8+ NKG2D+ | IFN-γ | JAK inhibitors |
| CTCL | Malignant CD4+ | IL-4, IL-13 | Various |
| Lichen planus | CD8+, Th1 | IFN-γ | Corticosteroids |
| Contact dermatitis | Th1 | IFN-γ, TNF | Corticosteroids, avoidance |
Key Clinical Pearls
| Topic | Pearl |
|---|
| Skin T cell population | ~20 billion T cells in skin; twice blood count |
| TRM cells | Explain site-specific recurrence (HSV, psoriasis, fixed drug) |
| Psoriasis = Th17 | IL-23/IL-17 axis central; targetable with biologics |
| AD = Th2 | IL-4/IL-13 blockade (dupilumab) is effective |
| Vitiligo = CD8+ CTL | IFN-γ signaling → JAK inhibitors emerging |
| CLA | Cutaneous lymphocyte antigen = skin tropism marker |
| Tregs | Hair follicle-associated; loss → alopecia areata, vitiligo |
Cross-References