Contributions
Abstract: P764
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: 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. In addition, we found that presence of peripheral CD4+ CTL is directly linked to MS disease severity and that this CD4+ subset holds value as a novel prognostic marker in MS.
Objectives: In this study, the mechanism behind disease progression due to CD4+ CTLs is investigated.
Methods: Co-culture systems of CD4+CD28- T cells and regulatory T cells (Treg) are used to investigate interaction between these subsets. In addition, flow cytometry is employed to characterize phenotype and function of CD4+ CTL.
Results: Here we show that CD4+CD28- T cells are phenotypically distinct from CD4+CD28+T cells, and that CD4+CD28- T cells evade Treg-mediated suppression in vitro. CD4+CD28- T cells display enhanced levels of pro-inflammatory molecules such as granzyme B, IFN-gamma, IL-1beta, IL-6, IL-22, and GM-CSF, but decreased levels of IL-10R and GITR. We further show that Tregs upregulate IL-10, granzyme B, CTLA-4, and IFN-gamma when exposed to the secretome of CD4+CD28- T cells. An in vitro co-culture system is currently being optimized to further analyze the effects of these differentially expressed factors, and elucidate how CD4+CD28- T cells affect Tregs and vice versa.
Conclusions: Our results suggest that CD4+CD28- T cells can evade Treg suppression through two distinct mechanisms: 1) by 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: P764
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Immunology
Introduction: 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. In addition, we found that presence of peripheral CD4+ CTL is directly linked to MS disease severity and that this CD4+ subset holds value as a novel prognostic marker in MS.
Objectives: In this study, the mechanism behind disease progression due to CD4+ CTLs is investigated.
Methods: Co-culture systems of CD4+CD28- T cells and regulatory T cells (Treg) are used to investigate interaction between these subsets. In addition, flow cytometry is employed to characterize phenotype and function of CD4+ CTL.
Results: Here we show that CD4+CD28- T cells are phenotypically distinct from CD4+CD28+T cells, and that CD4+CD28- T cells evade Treg-mediated suppression in vitro. CD4+CD28- T cells display enhanced levels of pro-inflammatory molecules such as granzyme B, IFN-gamma, IL-1beta, IL-6, IL-22, and GM-CSF, but decreased levels of IL-10R and GITR. We further show that Tregs upregulate IL-10, granzyme B, CTLA-4, and IFN-gamma when exposed to the secretome of CD4+CD28- T cells. An in vitro co-culture system is currently being optimized to further analyze the effects of these differentially expressed factors, and elucidate how CD4+CD28- T cells affect Tregs and vice versa.
Conclusions: Our results suggest that CD4+CD28- T cells can evade Treg suppression through two distinct mechanisms: 1) by 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.