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Cited by 132T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisDermatology and Skin Diseases

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Resident Memory T Cells in Autoimmune Skin Diseases

Open access
Ryan, Grace E., Harris, John E., Richmond, Jillian M.·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.652191PMC PMC8128248
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Abstract

Tissue resident memory T cells (TRM) are a critical component of the immune system, providing the body with an immediate and highly specific response against pathogens re-infecting peripheral tissues. More recently, however, it has been demonstrated that TRM cells also form during autoimmunity. TRM mediated autoimmune diseases are particularly destructive, because unlike foreign antigens, the self-antigens are never cleared, continuously activating self-reactive TRM T cells. In this article, we will focus on how TRMs mediate disease in autoimmune skin conditions, specifically vitiligo, psoriasis, cutaneous lupus erythematosus, alopecia areata and frontal fibrosing alopecia.

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Figure 1 Comparing and contrasting tissue resident memory and effector memory T cell phenotypes in skin. (A) Tissue resident memory (TRM, left, blue) cells downregulate S1P1 and CCR7, which are used for recirculation in the blood and lymph, when they take up residency in skin. TRMs use CD69, which was previously thought to be a marker of recently activated T cells, to block the expression of S1P1 on the cell surface and prevent exit from the tissue. CD103 is an integrin family member that is involved in skin and mucosal homing. It is not required for skin retention, but is expressed at a much higher rate in TRM cells in the epidermis compared to T cells in the dermis. CD49a has recently been used to distinguish the CD8+CD103+CD49a+ TRM T cells involved in mediating disease in vitiligo from the CD8+CD103+CD49a- TRM cells involved in psoriasis. TRM cells survive long-term in the nutrient-poor conditions of the skin by metabolizing free fatty acids. Increased expression of FABP4 and FABP5, fatty-acid binding proteins, allows TRM cells to take up larger amounts of exogenous free fatty acids for energy. IL-15 is required for TRM differentiation in skin, and TRM bear the CD122 and CD132 receptor chains. Keratinocytes can present IL-15 to TRM in trans on the CD215 receptor chain. TRM cells increase expression of PD1, which has a known inhibitory role in immune activation, and is important in maintaining immune homeostasis. Reduced expression of PD-1 in TRMs is associated with inappropriate chronic inflammation. CD69, which was historically thought to be a T cell activation marker, is stably expressed on Trm. (B) T effector memory (TEM, right, green) cells can also express varying levels of PD-1, making this marker useful more for determining exhaustion and/or chronic inflammation rather than tissue residence. TEM seem to rely more on CD127/IL-7 as a survival factor, which is in contrast to the IL-15 dependency of TRM. More often, they express CD49d than CD49a, though CD49a may also be used as a marker of degranulation. CD49d can interact intracellularly with CD44 to promote signaling, though CD44 is often present on both TRM and TEM and is used as a marker of “antigen experienced” T cells. CD45RO has historically been used to identify TEM in blood, and this short isoform of CD45 plays a role in T cell activation and signaling though a variety of pathways including JAK/STAT and Src. The transcription factors BLMP1 and ID2 promote expression of TEM-associated markers. Created with BioRender.com.
Figure 1 Comparing and contrasting tissue resident memory and effector memory T cell phenotypes in skin. (A) Tissue resident memory (TRM, left, blue) cells downregulate S1P1 and CCR7, which are used for recirculation in the blood and lymph, when they take up residency in skin. TRMs use CD69, which was previously thought to be a marker of recently activated T cells, to block the expression of S1P1 on the cell surface and prevent exit from the tissue. CD103 is an integrin family member that is involved in skin and mucosal homing. It is not required for skin retention, but is expressed at a much higher rate in TRM cells in the epidermis compared to T cells in the dermis. CD49a has recently been used to distinguish the CD8+CD103+CD49a+ TRM T cells involved in mediating disease in vitiligo from the CD8+CD103+CD49a- TRM cells involved in psoriasis. TRM cells survive long-term in the nutrient-poor conditions of the skin by metabolizing free fatty acids. Increased expression of FABP4 and FABP5, fatty-acid binding proteins, allows TRM cells to take up larger amounts of exogenous free fatty acids for energy. IL-15 is required for TRM differentiation in skin, and TRM bear the CD122 and CD132 receptor chains. Keratinocytes can present IL-15 to TRM in trans on the CD215 receptor chain. TRM cells increase expression of PD1, which has a known inhibitory role in immune activation, and is important in maintaining immune homeostasis. Reduced expression of PD-1 in TRMs is associated with inappropriate chronic inflammation. CD69, which was historically thought to be a T cell activation marker, is stably expressed on Trm. (B) T effector memory (TEM, right, green) cells can also express varying levels of PD-1, making this marker useful more for determining exhaustion and/or chronic inflammation rather than tissue residence. TEM seem to rely more on CD127/IL-7 as a survival factor, which is in contrast to the IL-15 dependency of TRM. More often, they express CD49d than CD49a, though CD49a may also be used as a marker of degranulation. CD49d can interact intracellularly with CD44 to promote signaling, though CD44 is often present on both TRM and TEM and is used as a marker of “antigen experienced” T cells. CD45RO has historically been used to identify TEM in blood, and this short isoform of CD45 plays a role in T cell activation and signaling though a variety of pathways including JAK/STAT and Src. The transcription factors BLMP1 and ID2 promote expression of TEM-associated markers. Created with BioRender.com.CC BY · PubMed Central
Figure 2 Evidence of TRM in autoimmune skin disease. (A) TRM in vitiligo. Melanocyte-specific TRM are present in vitiligo lesional skin. These cells express CD49a, CD69, CD103, and CD122 and produce IFNγ and chemokines upon encountering cognate antigen, such as gp100/Pmel-17, melan-A/MART-1, tyrosinase and/or tyrosinase-related proteins 1 & 2 presented on HLA-A2. Antigen-presenting cells (APCs) and keratinocytes also play a role in vitiligo immunopathogenesis, as they release cytokines in response to a myriad of stimuli and stressors. APCs produce IL-15 and trans-present it on CD215 to T cells, which bear the CD122 and CD132 chains of the IL-15 receptor. In vitiligo, our data support that TRM act as sentinel/alarm cells to induce recall responses against melanocytes. Blocking CD122 deprives the TRM of the IL-15 survival signal, thereby inhibiting their function and/or reducing their numbers to provide a durable treatment. A clinical trial is currently enrolling to test the potential of a commercially available anti-IL-15 antibody for vitiligo (NCT04338581). (B) TRM cells in CLE. Triggers such as UV radiation, infection, hormones, drugs and chemicals create an apoptotic and inflammatory environment (50). In lupus-prone individuals, antigen-presenting cells (APCs) migrate to the site of injury and ingest the cell debris and possible autoantigens. When the APCs present the autoantigens to self-reactive T cells and B cells, the autoimmune response is initiated, and disease occurs (51). Specifically, CD103+ TRM cells in the skin are positively correlated to disease severity and recurrence in patients. While TRM and T cell antigen specificities in lupus nephritis were recently described (52, 53), specificities of skin autoreactive T cells are unknown. A trial blocking anti-IL-17 antibody for DLE is recruiting (NCT03866317). (C) TRM cells in Psoriasis. CD69+ CD103+ TRM are present in psoriasis lesions. The production of cytokines such as IL-17a, IL-22, and Bcl-3 by these TRM cells lead to aberrant keratinocyte proliferation and differentiation. A recent study described melanocyte-specific T cells in psoriasis patients, though other specificities are unknown (54). Many trials for IL-17 family cytokine blockade, including IL-12/23, are ongoing. (D) TRM cells in Alopecia Areata (AA) and Cicatricial Alopecia (CA). NKG2D+ CD8+ T cells begin the disease process, breaching the immune privileged hair follicle through the activation of T cells and dendritic cells. Though the exact role of TRM cells in the pathogenesis of AA and FFA is unknown, it is clear that the production of IFNγ, CXCL9, and CXCL10 by T cells in the hair follicle is crucial in the development in disease. While clonal expansions of CD8 T cells have been detected with TCR sequencing (55), the antigen specificities of TRM in alopecias are still largely unknown (56). Trials for NK cell receptor and IL-2/9/15 inhibition are planned (NCT03532958 and NCT04740970). Created with BioRender.com.
Figure 2 Evidence of TRM in autoimmune skin disease. (A) TRM in vitiligo. Melanocyte-specific TRM are present in vitiligo lesional skin. These cells express CD49a, CD69, CD103, and CD122 and produce IFNγ and chemokines upon encountering cognate antigen, such as gp100/Pmel-17, melan-A/MART-1, tyrosinase and/or tyrosinase-related proteins 1 & 2 presented on HLA-A2. Antigen-presenting cells (APCs) and keratinocytes also play a role in vitiligo immunopathogenesis, as they release cytokines in response to a myriad of stimuli and stressors. APCs produce IL-15 and trans-present it on CD215 to T cells, which bear the CD122 and CD132 chains of the IL-15 receptor. In vitiligo, our data support that TRM act as sentinel/alarm cells to induce recall responses against melanocytes. Blocking CD122 deprives the TRM of the IL-15 survival signal, thereby inhibiting their function and/or reducing their numbers to provide a durable treatment. A clinical trial is currently enrolling to test the potential of a commercially available anti-IL-15 antibody for vitiligo (NCT04338581). (B) TRM cells in CLE. Triggers such as UV radiation, infection, hormones, drugs and chemicals create an apoptotic and inflammatory environment (50). In lupus-prone individuals, antigen-presenting cells (APCs) migrate to the site of injury and ingest the cell debris and possible autoantigens. When the APCs present the autoantigens to self-reactive T cells and B cells, the autoimmune response is initiated, and disease occurs (51). Specifically, CD103+ TRM cells in the skin are positively correlated to disease severity and recurrence in patients. While TRM and T cell antigen specificities in lupus nephritis were recently described (52, 53), specificities of skin autoreactive T cells are unknown. A trial blocking anti-IL-17 antibody for DLE is recruiting (NCT03866317). (C) TRM cells in Psoriasis. CD69+ CD103+ TRM are present in psoriasis lesions. The production of cytokines such as IL-17a, IL-22, and Bcl-3 by these TRM cells lead to aberrant keratinocyte proliferation and differentiation. A recent study described melanocyte-specific T cells in psoriasis patients, though other specificities are unknown (54). Many trials for IL-17 family cytokine blockade, including IL-12/23, are ongoing. (D) TRM cells in Alopecia Areata (AA) and Cicatricial Alopecia (CA). NKG2D+ CD8+ T cells begin the disease process, breaching the immune privileged hair follicle through the activation of T cells and dendritic cells. Though the exact role of TRM cells in the pathogenesis of AA and FFA is unknown, it is clear that the production of IFNγ, CXCL9, and CXCL10 by T cells in the hair follicle is crucial in the development in disease. While clonal expansions of CD8 T cells have been detected with TCR sequencing (55), the antigen specificities of TRM in alopecias are still largely unknown (56). Trials for NK cell receptor and IL-2/9/15 inhibition are planned (NCT03532958 and NCT04740970). Created with BioRender.com.CC BY · PubMed Central

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Metadata

Authors
Ryan, G. E., Harris, J. E., & Richmond, J. M.
Affiliations
University of Massachusetts Chan Medical School (US)
Corresponding author
  • Ryan, Grace E.
  • Richmond, Jillian M.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-05-03
Volume
12
Pages
652191-652191
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.652191
PMC
PMC8128248
OpenAlex
W3159116143
Cited by
132
References
95
Citations by year
2026: 22 · 2025: 32 · 2024: 33 · 2023: 26 · 2022: 16 · 2021: 3
FWCI
2.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship@UMassChan (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Dermatology Foundation
  • Lupus Research Alliance
  • National Institutes of Health
  • U.S. Department of Defense
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
Keywords
tissue-resident memory T cells, autoimmune skin disease, vitiligo, psoriasis, cutaneous lupus erythematosus, alopecia areata, frontal fibrosing alopecia, autoreactive T cells, autoantigens, autoimmunity
MeSH terms
Autoantigens, Autoimmune Diseases, Humans, Immunologic Factors, Immunologic Memory, Skin, Skin Diseases, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes

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