Contributions
Abstract: P1883
Type: Poster
Abstract Category: Late breaking news
A terminally differentiated subset of CD4+ T lymphocytes, characterized by loss of the costimulatory molecule CD28 and gain of cytotoxic activity, arises during aging and chronic inflammation. An age-inappropriate expansion of these cells has been found in autoimmune diseases like rheumatoid arthritis and multiple sclerosis (MS). Our group has recently published that CD4+ cytotoxic T lymphocytes (CTL) contribute to the pathology of autoimmune diseases, as we were able to show that expansion of CD4+ CTL exacerbates experimental autoimmune encephalomyelitis.
Here we show that CD4+CD28null T cells are phenotypically different from CD4+CD28+ T cells, and that CD4+CD28null T cells evade Treg mediated suppression in vitro. CD4+CD28null T cells display enhanced levels of pro-inflammatory molecules such as granzyme B, IFN-gamma, IL-1beta, IL-6, IL-22, and GM-CSF and decreased levels of IL-10R and GITR. Blocking of CD4+CD28null derived granzyme B or IFN-gamma completely restored the suppressive capacity of Tregs towards CD4+CD28null T cells. In contrast, blocking of IL-10R or GITR-L did not affect Treg mediated suppression. We further showed that Tregs upregulate IFN-gamma when exposed to the secretome of CD4+CD28null T cells. Blocking Treg-derived IFN-gamma partly reinstated Treg mediated suppression of CD4+CD28null T cells. These results suggest that CD4+CD28null T cells can evade Treg suppression through two distinct mechanisms: 1) becoming less susceptible to Treg activity and 2) by directly altering the functionality of Tregs. Elucidating these pathways may contribute to the development of novel therapeutic interventions specifically targeting age-inappropriate expansion of CD4+ CTL in autoimmune diseases like MS.
Disclosure:
Cindy Hoeks: nothing to disclose
Marjan Vanheusden: nothing to disclose
Liesbet Peeters: nothing to disclose
Piet Stinissen: nothing to disclose
Bieke Broux: nothing to disclose
Niels Hellings: nothing to disclose
Abstract: P1883
Type: Poster
Abstract Category: Late breaking news
A terminally differentiated subset of CD4+ T lymphocytes, characterized by loss of the costimulatory molecule CD28 and gain of cytotoxic activity, arises during aging and chronic inflammation. An age-inappropriate expansion of these cells has been found in autoimmune diseases like rheumatoid arthritis and multiple sclerosis (MS). Our group has recently published that CD4+ cytotoxic T lymphocytes (CTL) contribute to the pathology of autoimmune diseases, as we were able to show that expansion of CD4+ CTL exacerbates experimental autoimmune encephalomyelitis.
Here we show that CD4+CD28null T cells are phenotypically different from CD4+CD28+ T cells, and that CD4+CD28null T cells evade Treg mediated suppression in vitro. CD4+CD28null T cells display enhanced levels of pro-inflammatory molecules such as granzyme B, IFN-gamma, IL-1beta, IL-6, IL-22, and GM-CSF and decreased levels of IL-10R and GITR. Blocking of CD4+CD28null derived granzyme B or IFN-gamma completely restored the suppressive capacity of Tregs towards CD4+CD28null T cells. In contrast, blocking of IL-10R or GITR-L did not affect Treg mediated suppression. We further showed that Tregs upregulate IFN-gamma when exposed to the secretome of CD4+CD28null T cells. Blocking Treg-derived IFN-gamma partly reinstated Treg mediated suppression of CD4+CD28null T cells. These results suggest that CD4+CD28null T cells can evade Treg suppression through two distinct mechanisms: 1) becoming less susceptible to Treg activity and 2) by directly altering the functionality of Tregs. Elucidating these pathways may contribute to the development of novel therapeutic interventions specifically targeting age-inappropriate expansion of CD4+ CTL in autoimmune diseases like MS.
Disclosure:
Cindy Hoeks: nothing to disclose
Marjan Vanheusden: nothing to disclose
Liesbet Peeters: nothing to disclose
Piet Stinissen: nothing to disclose
Bieke Broux: nothing to disclose
Niels Hellings: nothing to disclose