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The authors investigate T-cell receptor (TCR) repertoire characteristics in association with clinical outcomes in systemic sclerosis (SSc) patients post-autologous hematopoietic stem cell transplantation (AHSCT). Topics mentioned include a decrease in TCR diversity when compared with pre-AHSCT, de novo naive T-cell production by reactivation of thymic function, and the role of infections acting in a genetically-susceptible person in SSc development. more...

Aging, sex, and genetics substantially affect human thymic function. Mining the Milieu Intérieur: Personalized medicine partly depends on understanding what causes variance even outside the context of overt disease. The Milieu Intérieur Consortium enrolled 1000 healthy adults to study how genetics and the environment influence the immune system. Clave et al. leveraged samples from this cohort to see how thymic output, known to decrease over time, is affected by other factors. In addition to seeing sex-dependent differences, a genome-wide association study revealed variants that were associated with thymic output, which was confirmed in an independent cohort and mouse models. The authors have also developed a Web application for other investigators to examine the Milieu Intérieur data. The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine. [ABSTRACT FROM AUTHOR] more...

The determinants of clinical responses after autologous hematopoietic stem cell transplantation (aHSCT) in systemic sclerosis (SSc) are still unraveled. We analyzed long-term immune reconstitution (IR) and T cell receptor (TCR) repertoire diversity in 10 SSc patients, with at least 6 years simultaneous clinical and immunological follow-up after aHSCT. Patients were retrospectively classified as long-term responders (A, n = 5) or non-responders (B, n = 5), using modified Rodnan's skin score (mRSS) and forced vital capacity (FVC%). All patients had similar severe SSc before aHSCT. Number of reinjected CD34+ cells was higher in group B versus A (P = 0.02). Long-term mRSS fall >25% was more pronounced in group A (P = 0.004), the only to improve long-term FVC% >10% (P = 0.026). There was an overall trend toward increased of T cell reconstitution in group B versus A. B cells had a positive linear regression slope in group A (LRS = 11.1) and negative in group B (LRS = -11.6). TCR repertoire was disturbed before aHSCT and the percentage of polyclonal families significantly increased at long-term (P = 0.046), with no difference between groups. Despite improved skin score after aHSCT in all SSc patients, pretransplant B cell clonal expansion and faster post-transplant T cell IR in long-term non-responder/relapsing patients call for new therapeutic protocols guided by IR analysis to improve their outcome. [ABSTRACT FROM AUTHOR] more...

Whether the efficacy of lenalidomide in the treatment of multiple myeloma (MM) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in patients with MM who had undergone autologous peripheral blood stem cell transplant (ASCT). Twenty-nine newly diagnosed patients with MM received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTRECs), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 − effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 − /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance. [ABSTRACT FROM AUTHOR] more...

Background & Aims: Crohn’s disease (CD) is an inflammatory bowel disease characterized by uncontrolled immune responses to bacterial flora, with excessive activation of T lymphocytes. MICA is a stress-induced major histocompatibility complex–related molecule expressed on normal intestinal epithelial cells (IECs) and recognized by the NKG2D-activating receptor on CD8+ T cells, γδ T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD. Methods: MICA expression was analyzed by flow cytometry on IECs isolated from patients with active inflammatory bowel disease and controls. NKG2D expression and function were analyzed on lamina propria and peripheral blood lymphocytes. Results: MICA expression was significantly increased on IECs in CD, with higher expression in macroscopically involved areas. A subset of CD4+ T cells expressing NKG2D was increased in the lamina propria from patients with CD compared with controls and patients with ulcerative colitis. CD4+NKG2D+ T cells with a Th1 cytokine profile and expressing perforin were increased in the periphery and in the mucosa in CD. CD4+NKG2D+ T-cell clones were functionally active through MICA-NKG2D interactions, producing interferon-γ and killing targets expressing MICA. IECs from patients with CD had the ability to expand this subset in vitro. CD4+NKG2D+ lamina propria lymphocytes from patients with CD highly expressed interleukin-15Rα, and interleukin-15 increased NKG2D and DAP10 expression in CD4+NKG2D+ T-cell clones. Conclusions: These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4+ T cells with inflammatory and cytotoxic properties in CD. [Copyright &y& Elsevier] more...

Rheumatic heart disease (RHD) is a sequel of post-streptococcal throat infection. Molecular mimicry between streptococcal and heart components has been proposed as the triggering factor of the disease, and CD4+ T cells have been found predominantly at pathological sites in the heart of RHD patients. These infiltrating T cells are able to recognize streptococcal M protein peptides, involving mainly 1–25, 81–103 and 163–177 N-terminal amino acids residues. In the present work we focused on the TCR β chain family (TCR BV) usage and the degree of clonality assessed by β chain complementarity-determining region (CDR)-3 length analysis. We have shown that in chronic RHD patients, TCR BV usage in peripheral blood mononuclear cells (PBMC) paired with heart-infiltrating T cell lines (HIL) is not suggestive of a superantigen effect. Oligoclonal T cell expansions were more frequently observed in HIL than in PBMC. Some major BV expansions were shared between the mitral valve (Miv) and left atrium (LA) T cell lines, but an in-depth analysis of BJ segments usage in these shared expansions as well as nucleotide sequencing of the CDR3 regions suggested that different antigenic peptides could be predominantly recognized in the Miv and the myocardium. Since different antigenic proteins probably are constitutively represented in myocardium and valvular tissue, these findings could suggest a differential epitope recognition at the two lesional heart sites after a common initial bacterial challenge. [ABSTRACT FROM PUBLISHER] more...

Using B-cell rearrangement excision circle measurements, we analyzed B-cell reconstitu-tion in a cohort of 243 patients who underwent allogeneic stem cell transplantation. Acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) transiently increased B-cell replication but decreased overall B-cell neogenesis with a clear difference in terms of kinetics. Moreover, the impact of aGVHD in the absence of cGVHD was transient, recovering at month 6 similar values as in patients who did not suffer from GVHD. Conversely, impact of cGVHD at month 12 in multivariate analysis was independent of the previous aGVHD effect on B-cell output. Finally, we showed in patients affected with cGVHD a higher B-cell division rate that correlates with an elevated BAFF/CD19+ B-cell ratio, supporting a B-cell hyperactivation state in vivo. [ABSTRACT FROM AUTHOR] more...

Abstract: Autologous hematopoietic stem-cell transplantation (HSCT) showed promising results for the treatment of primary severe autoimmune diseases (ADs). In this context, development of secondary AD after HSCT has exceptionally been observed, further questioning the roles of patient propensity for AD and of the HSCT procedure. Herein, we report new onset of myasthenia gravis 3 years after successful HSCT in a patient with severe systemic sclerosis, while in complete remission from her first AD. The de novo occurrence of secondary AD (myasthenia gravis) after HSCT was accompanied by the appearance of clonal T-cell expansions measured by the “immunoscope” technique in the context of an ongoing T-cell immune reconstitution. Secondary ADs are increasingly recognized after HSCT for AD. In our case, development of myasthenia followed clonal T-cell expansion. Detailed T-cell repertoire analysis may shed light on autoreactivity mechanisms after HSCT and may help to identify patients at risk. [Copyright &y& Elsevier] more...