GSE120904: Specific targeting of the common gamma chain blocks cooperative reprogramming of human tissue-resident cytotoxic T lymphocytes by IL-15 and IL-21

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GROUP CONDITION SAMPLES
Intestinal epithelial cells
GSM3418207 GSM3418214 GSM3418221 GSM3418228 GSM3418235
GSM3418206 GSM3418213 GSM3418220 GSM3418227 GSM3418234
GSM3418210 GSM3418217 GSM3418224 GSM3418231 GSM3418238
GSM3418211 GSM3418218 GSM3418225 GSM3418232 GSM3418239
GSM3418208 GSM3418215 GSM3418222 GSM3418229 GSM3418236
GSM3418209 GSM3418216 GSM3418223 GSM3418230 GSM3418237
GSM3418205 GSM3418212 GSM3418219 GSM3418226 GSM3418233
Intestinal intraepithelial cytotoxic T cells
GSM3418243 GSM3418253 GSM3418263 GSM3418273
GSM3418241 GSM3418251 GSM3418261 GSM3418271
GSM3418245 GSM3418255 GSM3418265 GSM3418275
GSM3418242 GSM3418252 GSM3418262 GSM3418272
GSM3418247 GSM3418257 GSM3418267 GSM3418277 GSM3418281 GSM3418285 GSM3418289
GSM3418249 GSM3418259 GSM3418269 GSM3418279 GSM3418283 GSM3418287 GSM3418291
GSM3418244 GSM3418254 GSM3418264 GSM3418274
GSM3418246 GSM3418256 GSM3418266 GSM3418276 GSM3418280 GSM3418284 GSM3418288
GSM3418240 GSM3418250 GSM3418260 GSM3418270
GSM3418248 GSM3418258 GSM3418268 GSM3418278 GSM3418282 GSM3418286 GSM3418290
Description

Submission Date: Oct 05, 2018

Summary: The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.

GEO Accession ID: GSE120904

PMID: 31622625

Description

Submission Date: Oct 05, 2018

Summary: The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.

GEO Accession ID: GSE120904

PMID: 31622625

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