De La Cruz Diaz, Jacinto S
(2021)
The role of epidermal TGFβ activating integrins in Langerhans cell migration.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In addition to providing a physical barrier, the epidermis provides a niche for the long-term residency of Langerhans cells (LC). LC provide protection by priming elements of the adaptive immune system, but they can also participate in the maintenance and development of autoimmune and inflammatory diseases. Within the epidermis, LC possess the ability to migrate from the skin epidermis to regional lymph nodes (LN). At steady-state, LC migrate to LN transporting self and potentially commensal-derived antigen to promote the development of peripheral tolerance. During infection, LC transport potential pathogen-derived antigens and prime naïve adaptive immune responses. Our understanding of LC biology has predominantly been focused on their differentiation and recruitment into the epidermis. The mechanisms that allowed for the long-term retention of these leukocytes has not been extensively studied. Hence, elucidating the mechanisms by which LC maintain their epidermal residency and mediate migration is of great therapeutic interest and will extend our knowledge in LC biology.
We have previously shown that integrins ανβ6 and ανβ8 on keratinocytes (KCs) cleave LAP-TGFβ1 to its active form TGFβ1 (Transformative Growth Factor βeta 1), which acts on the TGFβ receptor of LCs to maintain their long-term residency within the skin epidermis. We have also demonstrated that selective expression of a ligand independent constitutively active form of TGFβRI, inhibits LC migration during homeostasis and in response to ultraviolet light in the B spectrum (UVB) exposure. Interestingly, UVB treatment resulted in the loss of epidermal integrins ανβ6 and ανβ8 on KCs. However, whether inflammation induced LC migration acts through a similar mechanism remains unclear. Thus, we propose to test the hypothesis that inflammatory stimuli mediate LC migration from the epidermis through the inhibition of KC-integrin mediated TGF-β activation.
In this dissertation, we demonstrate that LC migration in response to inflammatory stimuli was also inhibited by ligand independent TGFβRI signaling. Unlike UVB stimulation which reduced KCs expression of avβ6, in vitro and in vivo exposure to TNF-α or IL-1β increased avβ6 mRNA and protein expression by KCs. This resulted in increased KCs mediated transactivation of latent TGFβ. Expression of avβ8 was largely unchanged. These findings demonstrate that ligand independent TGFβRI signaling in LC can overcome inflammatory migration stimuli, but reduced KCs-mediated transactivation of latent TGFβ by KCs may only drive LC migration during homeostasis and in response to UVB stimulation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
5 November 2021 |
| Date Type: |
Publication |
| Defense Date: |
23 June 2021 |
| Approval Date: |
5 November 2021 |
| Submission Date: |
18 August 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
97 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Langerhans cell, keratinocytes, TGFβ-activating integrins, ανβ6, ανβ8 |
| Date Deposited: |
05 Nov 2021 15:34 |
| Last Modified: |
05 Nov 2021 15:34 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41694 |
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