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THE ROLE OF CD137POS T REGULATORY CELLS AND SOLUBLE CD137 IN TYPE ONE DIABETES.

Kachapati, Kritka (2013) THE ROLE OF CD137POS T REGULATORY CELLS AND SOLUBLE CD137 IN TYPE ONE DIABETES. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

CD137 is an inducible T cell costimulatory molecule, and a subset of CD4+CD25+ T regulatory cells constitutively express CD137 (CD137pos Tregs). The nonobese diabetic (NOD) mouse spontaneously develops Type one diabetes (T1D), and genetic mapping studies have implicated CD137 as a candidate gene in the chromosome four Idd9.3 interval. We show that anti-CD137 treatment protects NOD mice from diabetes. Anti-CD137 antibody specifically binds to CD137pos Tregs cells in vivo. Antibody treatment increases the percentage of Tregs and these cells prevent diabetes in transfer studies. Depleting CD4+CD25+ T cells eliminated anti-CD137 mediated diabetes protection. These studies demonstrate the importance of the CD137pos Treg subset, which express the same amount of Foxp3 as CD137neg Tregs but are functionally superior in contact dependent and independent suppression assays in vitro. Congenic NOD.B10 Idd9.3 mice (that have a 40% decreased incidence of diabetes compared to NOD), have significantly increased numbers of peripheral CD137pos Tregs compared to NOD. Mixed bone marrow chimeras using the two allotypically marked strains showed an intrinsic cellular basis for the accumulation of B10 Idd9.3 CD137pos Tregs. While CD137pos Tregs from NOD and NOD.B10 Idd9.3 showed no suppressive differences, the accumulation of the functionally superior Treg subset enables enhanced immunosuppression in the congenic mice. We show that CD137pos Tregs are the major T cell source for the alternatively spliced CD137 isoform, soluble CD137, which causes reduced T cell proliferation. Increased serum soluble CD137 in NOD.B10 Idd9.3 versus NOD mice associates soluble CD137 with diabetes protection. Anti-CD137 treatment increases serum soluble CD137. Soluble CD137-Fc directly reduces CD4pos T cells proliferation in a CD137 ligand dependent manner. We used a lentiviral approach to produce recombinant soluble CD137 in vitro. The purified soluble CD137 is predominantly a dimer, and directly suppresses CD4 T cell proliferation. Soluble CD137 protein prevents diabetes and significantly reduces insulitis in NOD. Our data shows that diabetes protection by both anti-CD137 treatment and in NOD.B10 Idd9.3 mice is associated with expansion of suppressive CD137pos Tregs and subsequent accumulation of immunosuppressive soluble CD137. These studies establish the importance of the CD137pos Treg subset and soluble CD137 in T1D and immunobiology.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kachapati, Kritkakkachapti@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRidgway, Williamwridg1@gmail.com
Committee MemberRay, Anuradha raya+@pitt.edu RAYA
Committee MemberLu, Binfeng binfeng+@pitt.edu BINFENG
Committee MemberPiganelli, Johnjdp51+@pitt.edu JDP51
Committee MemberMassimo, TruccoHnidkaP+@pitt.edu
Committee MemberScott, Donald donald.scott@mssm.edu
Date: 3 January 2013
Date Type: Publication
Defense Date: 11 December 2012
Approval Date: 3 January 2013
Submission Date: 14 December 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 178
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Diabetes, NOD mouse, CD137, Soluble CD137, congenic mouse
Date Deposited: 04 Jan 2014 06:00
Last Modified: 03 Jan 2018 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/16984

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