Diabetic foot ulcerations are a debilitating complication common to type 1 and 2 diabetes. There is a critical need for studies that identify how diabetes affects cell-cell interactions in epithelial tissues such as the skin, which are very susceptible to damage. Murine skin 34 T cells, also known as dendritic epidermal T cells (DETC), play roles in skin homeostasis and wound repair. The complex cross-talk between the activating keratinocytes and the responding DETC is mediated by receptor expression and growth factor production. Our long-term goal is to determine how diabetes negatively impacts the immune system, with a special focus on epithelial T cell populations. This application will examine how type 2 diabetes alters the survival and function of DETC and whether this can be reversed therapeutically. The working hypothesis is that DETC are chronically stimulated by insulin resistant keratinocytes rendering the DETC apoptotic and eventually anergic. This hypothesis is based on preliminary results, which show that the normal cross-talk between DETC and keratinocytes is altered in diabetic skin. The following specific aims are proposed: (1) determine why DETC are diminished in the skin of mice with type 2 diabetes, (2) identify the contribution of keratinocyte-DETC cross-talk to DETC dysfunction in diabetic mice, and (3) restore DETC numbers and function in diabetic mice. Once we identify how DETC are suppressed in diabetic mouse skin we may be able to restore activation and exploit their wound healing potential.
These specific aims will be tested by examining how DETC numbers decline in diabetic skin and whether the remaining DETC are rendered functionally unresponsive or anergic. Anergy would affect the ability of DETC to proliferate and secrete factors during normal homeostasis and wound repair. Cross-talk between DETC and keratinocytes will be examined during type 2 diabetes to identify whether keratinocytes play a role in the suppression of DETC. Finally, two approaches will be taken to restore normal DETC activation in diabetic mice. First, the DETC will be targeted by treating mice with IL-2 cytokine therapy to restore DETC activation. The second approach involves improving insulin responsiveness to allow the keratinocytes to normalize, which may indirectly restore DETC function. Defining the impact of type 2 diabetes on T cell- epithelial cell interactions will greatly advance our knowledge of how this condition may lead to immune dysfunction. This will lead to the development of novel strategies to promote wound repair and other complications of diabetes.

Public Health Relevance

T cells in the skin are stimulated by damaged keratinocytes to produce growth factors important for wound repair. Chronic non-healing wounds are a serious complication of diabetes with devastating consequences. The goal of our research is to determine how type 2 diabetes alters T cell survival and function in the epithelia and whether this process can be reversed therapeutically to promote healing of chronic wounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080048-06
Application #
8420547
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2009-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$261,099
Indirect Cost
$90,796
Name
California State University San Marcos
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
176262681
City
San Marcos
State
CA
Country
United States
Zip Code
92078
Cheung, Kitty P; Taylor, Kristen R; Jameson, Julie M (2012) Immunomodulation at epithelial sites by obesity and metabolic disease. Immunol Res 52:182-99
Taylor, Kristen R; Costanzo, Anne E; Jameson, Julie M (2011) Dysfunctional ýýýý T cells contribute to impaired keratinocyte homeostasis in mouse models of obesity. J Invest Dermatol 131:2409-18
Taylor, Kristen R; Mills, Robyn E; Costanzo, Anne E et al. (2010) Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS One 5:e11422
Havran, Wendy L; Jameson, Julie M (2010) Epidermal T cells and wound healing. J Immunol 184:5423-8
Jameson, Julie M; Cruz, John; Costanzo, Anne et al. (2010) A role for the mevalonate pathway in the induction of subtype cross-reactive immunity to influenza A virus by human gammadelta T lymphocytes. Cell Immunol 264:71-7