Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes

• Published in: Cellular immunology Vol. 319; pp. 3 - 9
• Main Authors: Long, S. Alice, Thorpe, Jerill, Herold, Kevan C., Ehlers, Mario, Sanda, Srinath, Lim, Noha, Linsley, Peter S., Nepom, Gerald T., Harris, Kristina M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.09.2017
• Subjects: Adolescent; Adult; Anti-CD3 monoclonal antibody; Antibodies, Monoclonal, Humanized - therapeutic use; C-Peptide - agonists; C-Peptide - genetics; C-Peptide - immunology; CD3 Complex - genetics; CD3 Complex - immunology; CD57 Antigens - genetics; CD57 Antigens - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Child; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Gene Expression; Humans; Hypoglycemic Agents - therapeutic use; Immune tolerance; Immune Tolerance - drug effects; Immunomodulation; Immunotherapy; Immunotherapy - methods; Interleukin-7 Receptor alpha Subunit - genetics; Interleukin-7 Receptor alpha Subunit - immunology; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Male; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; T cell inactivation; T lymphocyte; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Trans-Activators - genetics; Trans-Activators - immunology; Type 1 diabetes; Anti-CD3 monoclonal antibody; T lymphocyte; Type 1 diabetes; T cell inactivation; Immunotherapy; Immune tolerance
• ISSN: 0008-8749; 1090-2163; 1090-2163
• DOI: 10.1016/j.cellimm.2017.07.007

•Duration and complexity of T cell modulation with teplizumab in type 1 diabetes.•An overall reduction in T cell populations was observed with each treatment course.•Teplizumab coordinated increases in inhibitory molecules on CD4 and CD8 T cells.•Each treatment course reduced expression of CD127/IL-7Ra on CD8 T cell subsets.•Immunological changes associated with treatment success in ADA-negative subjects. The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57−KLRG1−PD-1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57-KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success.