Session Information
Title: T-cell Biology and Targets in Autoimmune Disease: Signaling Pathways in T-cell Differentiation
Session Type: Abstract Submissions (ACR)
Background/Purpose: Absence of co-stimulation in the presence of TCR-stimulation has been proposed to induce tolerance via deletion or anergy. Abatacept is a CTLA-4-Ig molecule that binds with high affinity to CD80/86 on antigen presenting cells (APC). It modulates CD28-mediated T cell co-stimulation and is currently approved for the treatment of rheumatoid arthritis, however it remains unclear whether its use leads to the development of immunological tolerance. The aim of this study was to investigate in vivo the capacity of abatacept to regulate development of antigen-specific immunological tolerance.
Methods: In order to generate antigen specific tolerised CD4+ T cells, DO11.10 RAG2-/- mice, which have a CD4 cells specific for ovalbumin (OVA), were fed with OVA in their drinking water (50mg/ml) for 10 days. Priming was induced by s.c. injection of OVA in CFA in the presence of abatacept or control IgG (10mg/kg). The functionality of the generated CD4 populations was confirmed by their ability to respond to antigen rechallenge after adoptive transfer into BALB/c mice. The phenotype of purified CD4 and CD11c cells was assessed by flow cytometry, ELISA and complemented by detailed full genome transcriptional profiling.
Results:
While T cells tolerised by ovalbumin feeding were unable to produce IL-2 after ex-vivo restimulation, T cells primed in the presence of abatacept produced copious amounts of this cytokine and resembled naïve T cells exposed to antigen for the first time in this respect. Tolerised T cell populations exhibited a significantly higher proportion of TREG and CTLA-4+ cells compared with naïve, primed or ‘primed in the presence of abatacept’ T cells. The latter were characterised by the absence of TREG, more resembling naïve rather than tolerised T cells. However, abatacept treatment significantly reduced the expression of T cell markers (ICOS, CD71 and CD44) compared with primed and orally tolerised groups. When these T cells were adoptively transferred to BALB/c mice and rechallenged with OVA, only the orally tolerised CD4 cells failed to expand to antigen, suggesting that abatacept treatment does not induce anergy. Furthermore, T cells isolated from abatacept treated mice had a unique transcriptional profile, distinct from naïve, tolerant and primed T cells. Crucially we observed that this state is accompanied by an inhibition of the activation of dendritic cells at the transcriptional level, indicating a level of licensing of these cells by T cells. These results demonstrate that Abatacept treatment significantly modulates T-DC communication resulting in defective cell priming in vivo and a unique transcriptional profile which is distinct from anergic tolerance.
Conclusion:
This study provides insight into the mode of action of Abatacept and its bidirectional impact upon both T cells and DC. We demonstrate that while abatacept does not induce T cell anergy, it generates a distinct T cell phenotype that most resembles naïve T cells and potentially modulates the function of APCs. This could have significant implications when considering its application in rheumatoid arthritis and other autoimmune conditions.
Disclosure:
A. Patakas,
None;
R. R. Ji,
Bristol-Myers Squibb Co,
3;
W. Weir,
None;
S. Connolly,
Bristol-Myers Squibb Co,
3;
S. G. Nadler,
Bristol-Myers Squibb Co,
3;
J. M. Brewer,
Bristol-Myers Squibb Co,
2;
I. B. McInnes,
Bristol-Myers Squibb Co,
2;
P. Garside,
Bristol-Myers Squibb Co,
2.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abatacept-is-highly-effective-at-inhibiting-t-cell-priming-and-induces-a-unique-transcriptional-profile-in-cd4-t-cells/