Laboratory of Immunophysiology

Supervisor

António Pires da Silva Baptista

Project description

Immune tolerance involves self-reactive T cell deletion in the thymus, and peripheral constraint of self-reactive escapees by regulatory T cells (Tregs). The latter occurs mostly in secondary lymphoid organs such as lymph nodes, where Tregs actively limit self-reactive T cell activation by stealing of IL2. We have shown that lymph node fibroblastic reticular cells (FRCs) mediate intranodal Treg maintenance via MHC-II-dependent antigen presentation. In this project, we aim to 1) unravel the molecular mechanisms that determine MHC-II expression by FRCs; 2) determine which self-antigens are presented by FRCs (examining possible region-specific patterns of self-antigen presentation); and 3) determine the influence of immune activation in FRC MHC-II and self-antigen expression.

Candidate profile

This research involves mouse studies (surgery and adoptive cell transfer), wet-lab techniques (cell culture, flow cytometry and imaging), and analysis of sequencing and spatial data. The candidate is expected to have basic knowledge of bioinformatics (coding in R).

Suggested reading

• Wong HS, Park K, Gola A, Baptista AP, Miller CH, Deep D, Lou M, Boyd LF, Rudensky AY, Savage PA, Altan-Bonnet G, Tsang JS, Germain RN. A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells. Cell 2021 184(15):3981-3997.e22. [pubmed] [doi]
• Baptista AP, Roozendaal R, Reijmers RM, Koning JJ, Unger WW, Greuter M, Keuning ED, Molenaar R, Goverse G, Sneeboer MM, den Haan JM, Boes M, Mebius RE. Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. Elife 2014 19;3:e04433.[pubmed] [doi]
• Levine AG, Hemmers S, Baptista AP, Schizas M, Faire MB, Moltedo B, Konopacki C, Schmidt-Supprian M, Germain RN, Treuting PM, Rudensky AY. Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity. J Exp Med 2017 6;214(3):609-622. [pubmed] [doi]
• Baptista AP, Gola A, Huang Y, Milanez-Almeida P, Torabi-Parizi P, Urban JF Jr, Shapiro VS, Gerner MY, Germain RN. The Chemoattractant Receptor Ebi2 Drives Intranodal Naive CD4+ T Cell Peripheralization to Promote Effective Adaptive Immunity. Immunity 2019 50(5):1188-1201.e6. [pubmed] [doi]

Supervisor

António Pires da Silva Baptista

Project description

Lymphoid-myeloid crosstalk and cooperation are essential for host protection against infection. Involving multiple signaling pathways, this communication is thought to involve sensing of infection by myeloid cells which in turn activate lymphocytes, followed by feedback regulation of the myeloid response by the activated lymphocytes. Notably, in the absence of infection, this communication is thought to be limited, with both lymphoid and myeloid compartments mostly behaving independently from each other.  Here, using mice with multiple deficiencies in lymphoid cells, reconstitution approaches involving cellular transplantation, single-cell RNA sequencing and genetic screens we aim to 1) determine the influence of lymphoid cells in quantitative and qualitative myeloid cell homeostasis; 2) determine the signaling pathways involved in setting the appropriate homeostatic lymphocyte-myeloid balances; and 3) determine how myeloid cells “raised” in the absence of lymphocyte conditioning recognize and respond to infectious stimuli.

Candidate profile

This research involves mouse protocols (adoptive cell transfers, infections), wet-lab techniques (cell culture, genetic editing, flow cytometry and imaging), and analysis of sequencing data. The candidate is expected to have basic knowledge of mouse handling and genetics.

Suggested reading

• Baptista AP, Gola A, Huang Y, Milanez-Almeida P, Torabi-Parizi P, Urban JF Jr, Shapiro VS, Gerner MY, Germain RN. The Chemoattractant Receptor Ebi2 Drives Intranodal Naive CD4+ T Cell Peripheralization to Promote Effective Adaptive Immunity. Immunity 2019 50(5):1188-1201.e6. [pubmed] [doi]
• Vanderkerken M, Baptista AP, De Giovanni M, Fukuyama S, Browaeys R, Scott CL, Norris PS, Eberl G, Di Santo JP, Vivier E, Saeys Y, Hammad H, Cyster JG, Ware CF, Tumanov AV, De Trez C, Lambrecht BN. ILC3s control splenic cDC homeostasis via lymphotoxin signaling. J Exp Med 2021 218(5):e20190835. [pubmed] [doi]
• Jarick KJ, Topczewska PM, Jakob MO, Yano H, Arifuzzaman M, Gao X, Boulekou S, Stokic-Trtica V, Leclère PS, Preußer A, Rompe ZA, Stamm A, Tsou AM, Chu C, Heinrich FR, Guerra GM, Durek P, Ivanov A, Beule D, Helfrich S, Duerr CU, Kühl AA, Stehle C, Romagnani C, Mashreghi MF, Diefenbach A, Artis D, Klose CSN. Non-redundant functions of group 2 innate lymphoid cells. Nature 2022 611(7937):794-800. [pubmed] [doi]
• Mao K, Baptista AP, Tamoutounour S, Zhuang L, Bouladoux N, Martins AJ, Huang Y, Gerner MY, Belkaid Y, Germain RN. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 2018 554(7691):255-259. [pubmed] [doi]