All Publications

  • Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Science translational medicine Borna, Š., Lee, E., Nideffer, J., Ramachandran, A., Wang, B., Baker, J., Mavers, M., Lakshmanan, U., Narula, M., Garrett, A. K., Schulze, J., Olek, S., Marois, L., Gernez, Y., Bhatia, M., Chong, H. J., Walter, J., Kitcharoensakkul, M., Lang, A., Cooper, M. A., Bertaina, A., Roncarolo, M. G., Meffre, E., Bacchetta, R. 2023; 15 (727): eadg6822


    Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

    View details for DOI 10.1126/scitranslmed.adg6822

    View details for PubMedID 38117899

  • Sex-Linked Differences in Malaria Risk Across the Lifespan. Current topics in microbiology and immunology Briggs, J., Murray, M., Nideffer, J., Jagannathan, P. 2023; 441: 185-208


    Despite the high burden of malaria worldwide, there is surprisingly scarce research on sex-based differences in malaria outside of pregnancy. A more thorough understanding of sexual dimorphism in malaria, and what underlies these sex-based differences, could elucidate the underlying mechanisms driving malaria pathogenesis and has the potential to inform malaria control efforts, including new vaccines. This review summarizes our current understanding of sex-based differences in the epidemiology of malaria across the lifespan, potential sex- or gender-based mechanisms driving these differences, and the knowledge gaps that need to be addressed.

    View details for DOI 10.1007/978-3-031-35139-6_7

    View details for PubMedID 37695429

    View details for PubMedCentralID 4157516

  • Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria. Science translational medicine Ty, M., Sun, S., Callaway, P. C., Rek, J., Press, K. D., van der Ploeg, K., Nideffer, J., Hu, Z., Klemm, S., Greenleaf, W., Donato, M., Tukwasibwe, S., Arinaitwe, E., Nankya, F., Musinguzi, K., Andrew, D., de la Parte, L., Mori, D. M., Lewis, S. N., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Blish, C., Utz, P. J., Khatri, P., Dorsey, G., Kamya, M., Boyle, M., Feeney, M., Ssewanyana, I., Jagannathan, P. 2023; 15 (680): eadd9012


    Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.

    View details for DOI 10.1126/scitranslmed.add9012

    View details for PubMedID 36696483

  • Type I regulatory T cells in malaria: of mice and men Jason Nideffer, Prasanna Jagannathan JOURNAL OF CLINICAL INVESTIGATION Nideffer, J., Jagannathan, P. 2023; 133 (1)


    Type I regulatory T (Tr1) cells are a population of regulatory CD4+ T cells implicated in the suppression of pathological immune responses across multiple diseases, but a unifying transcriptional signature of Tr1 identity across disease contexts has not been characterized. In this issue of the JCI, Edward, Ng, and colleagues identified a conserved transcriptional signature that distinguished Tr1 (IL-10+IFN-γ+) from Th1 (IL-10-IFN-γ+) cells in human and mouse malaria. This signature implicated genes encoding inhibitory receptors - including CTLA-4 and LAG-3 - and transcription factors - including cMAF. The authors identified coinhibitory receptor expression that distinguished Tr1 cells from other CD4+ T cell subsets. Furthermore, cMAF - and, to a lesser extent, BLIMP-1 - promoted IL-10 production in human CD4+ T cells. BLIMP-1 also played a role in supporting the expression of inhibitory receptors. These findings describe a few key features that seem to be conserved by Tr1 cells across multiple species, disease contexts, and marker definitions.

    View details for DOI 10.1172/JCI166019

    View details for Web of Science ID 000992543100002

    View details for PubMedID 36594472

    View details for PubMedCentralID PMC9797330