Findings highlight the important function of keratinocytes in determining the epidermal occupancy of dendritic cells and resident memory T cells and provide a potential therapeutic target to deplete these cells in disease states.

1. T cells, dendritic cells, autoimmunity
and the hair follicle
Daniel H. Kaplan
Departments of Dermatology and
Immunology
University of Pittsburgh

2. Skin-resident Immune Cells
Langerhans Cells
(LC)
CD103+ dDC CD11b+ dDC
TCR γδ T cell
CD8+ TRM
DETC
ILC
CD4+ TRM
Nerves

3. Langerhans Cells
(LC)
CD103+ dDC CD11b+ dDC
TCR γδ T cell
CD8+ TRM
DETC
ILC
CD4+ TRM
Nerves
What determines Epidermal
Residence?
Skin-resident Immune Cells

4. LC and TGFb
TGFb1-/- mice lack LC
TGFb1 likely required by LC
precursors
TGFb1 promotes LC
differentiation in vitro
TGFb1 is required for LC
development

5. Adult mouse LC require TGFβ for
epidermal residence
Bobr PNAS 2012

6. Adult human LC require TGFβ for
epidermal residence
control losartan
0
5
10
15
20
25
30
35
NumberLCpermm
****

7. TGFβ1 and TGFβRII Ablation in
Adult LC Promotes LC Migration
Bobr PNAS 2012
huLangerin-CreERT2 x TGFβf/f huLangerin-CreERT2 x TGFβRIIf/f
LC require autocrine/paracrine TGFβ
for epidermal residence

8. Adapted from Wipff et al. EJCB, 2008.
TGF-β1 Secreted as Latent Complex
In skin epidermis only
αvβ6 and αvβ8 activate
latent TGFβ1
Yang, JBC 2007

9. Activation of TGFβ by αvβ6 required
for LC epidermal residence

10. Interfollicular epidermis (IFE)
Isthmus (IM)
Bulge
DAPI Langerin
CD45- Sca1-
Subsets of Keratinocytes
Adapted from Heath, NI 2012
Nagao, NI 2012

11. αvβ8 and αvβ6 are expressed by
different keratinocytes
LC IFE IM Bulge
0.0
0.5
1.0
1.5
2.0 Itgβ6
Expression/HPRT
Itgβ8
A B

12. αvβ6 is Required for LC in
Interfollicular Epidermis

13. αvβ8 is required for LC in
follicular epidermis
Itgβ8∆KC
WT
IFE IFE
IM
IM
E

14. Itgβ6-/-WT Itgβ6-/-xItgβ8∆KC
0
100
200
300
400
LCperfield
WT Itgβ6-/-xItgβ8∆KC
Itgβ6-/-
Itgβ6 and Itgβ8 determine LC
patterning through TGFβ activation

15. Loss of TGFβ signaling is required
for UV-induced LC migration

16. UV reduced Integrin expression by
KC
KC
KC
+U
V
Itgβ6expression
Itgβ8expression
KC
KC
+U
V
0.00
0.25
0.50
0.75
1.00
1.25
0.00
0.05
0.10
0.15
0.20
KC
KC+UV
0.0
0.5
1.0
1.5
RLU
***
***
***

17. Loss of TGFβ signaling is required
for UV-induced LC migration

18. What about other epidermal cells?
Langerhans Cells
(LC)
CD8+ TRM
DETC
CTCL Psoriais Fixed Drug Vitiligo Alopecia Areata

19. Trm epidermal residence requires
avβ6 and avβ8
Trm in dermis, LN, spleen unaffected by absence of avβ6

20. avβ6 blockade depletes epidermal
and SI epithelial Trm

21. avb6/b8
KC
TGFb
R
TGFb
TGFb-LAP
Trm
TGFb
R
TGFb-LAP
LC
Model
Retention of LC and Trm in Epidermis
Epidermal retention
Epidermal retention
TGFb
LC migration
Loss of epidermal maintenance
Migratory signal

22. avb6/b8
KC
TGFb
R
TGFb
TGFb-LAP
Trm
TGFb
R
TGFb-LAP
LC
Model
Retention of LC and Trm in Epidermis
Epidermal retention
Epidermal retention
TGFb
Keratinocytes directly control epithelial retention of
leukocytes via a novel mechanism of intercellular
communication
• LC migration is cell extrinsic (i.e. Keratinocytes
determine LC migration)
• Avβ6 and Avβ8 are spatially distinct and regulated
• DC and T cell retention varies by epidermal anatomy
and could be differently regulated
• Targeting TGFβ or its activation could be used to deplete
TRM from epidermis (e.g. Alopecia Areata, Psoriasis,
CTCL, Vitiligo)
Mohammed et al. Nature Immunology, 2016

23. Acknowledgements
University of Minnesota
Javed Muhammed
Aleh Bobr
Nathan Welty
Brian Chicione
Sakeen Kashem
Botond Igyarto
Brian Astry
David Masopust
Lalit Beura
NIAMS Dermatology
Foundation
Sloan Kettering Cancer
Ming Li
INSERM, Lyon
Laurent Bartholin
UCSF
Dean Sheppard
NYU
Dan Rifkin
Mayo Clinic
Alina Bridges