ESPE Yearbook of Paediatric Endocrinology

J Clin Invest. 2024;134(18). PMID: 39137044

Brief summary: The phenotypes, transcriptome, and repertoire of peripheral blood CD8+ T cells were analysed in individuals before and up to 18 months after a single 14-day course of teplizumab. At 3 months, activation signatures were observed in CD4⁺ and CD8⁺ T cells. By 18 months, responders showed reduced activation gene expression and increased markers of exhaustion and regulation. Unlike the placebo group, the frequency of autoantigen-reactive CD8⁺ T cells did not expand with teplizumab.

Since November 2022, Teplizumab (an anti-CD3 monoclonal antibody) has been the first and only disease modifying drug approved by the Food and Drug Administration (FDA) for individuals with presymptomatic stage 2 type 1 diabetes (T1D) (individuals with 2 or more autoantibodies and dysglycemia) 8 years or older (1). The main trial which led to this approval was the TrialNet Teplizumab Prevention Study (TN10), a randomized placebo-controlled trial which showed that a single 14-day course of teplizumab caused a significant delay in progression to stage 3 T1D in people with presymptomatic stage 2 T1D, with 36% of participants remaining disease-free for over 5 years (2).

This study used single-cell RNA sequencing and reports detailed immunological analyses in peripheral blood cells from TN10 participants (n= 68), aiming to further understand the effects of teplizumab treatment and identify cellular signatures associated with long-term responses (up to 18 months) after a single course of the drug. The study showed an increase in transcriptomic signatures of CD8⁺ T cell activation at 3 months post-treatment, followed by a decline and differentiation into effector cells with features of exhaustion and regulation by 18 months. Similar changes occurred in CD4⁺ T cells, with initial activation and a subsequent decline in responders at 18 months. Teplizumab treatment also reduced the expression of IL7R in CD8⁺ T cells, a receptor required for these cells’ growth and expansion. Additionally, there was reduced expansion of autoantigen-reactive CD8⁺ T cells in teplizumab- compared placebo-treated participants.

These data suggest that signals delivered by teplizumab affect multiple immune cell subsets, promoting the differentiation of CD8⁺ T cells into regulatory and exhausted phenotypes, and preventing the expansion of autoantigen-specific CD8⁺ T cells. These mechanisms may underlie the induction of operational tolerance following a single course of teplizumab treatment. Further studies comparing individuals protected from diabetes for extended periods with healthy controls may identify key immunological signatures associated with long-term tolerance.

References: 1. Saleem MR, Khan MT. Teplizumab: a promising intervention for delaying type 1 diabetes progression. Front Endocrinol (Lausanne) 2025;16:1533748.2. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med 2019;381(7):603-613.