Luís Graça Lab

• Regulatory T cells and Immune tolerance
• The biology of germinal centres, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells and the regulation of antibody production
• Clinical Research
• Autoimmunity
• Allergy
• Transplantation
• Vaccines
• Infection and Immunity
• Computational biology and bioinformatics
• Epidemiology

Kumar S, Basto AP, Ribeiro F, Almeida SCP, Campos P, Peres C, Pulvirenti N, Al-Khalidi S, Kilbey A, Tosello J, Piaggio E, Russo M, Gama-Carvalho M, Coffelt SB, Roberts EW, Geginat J, Florindo HF, Graca L. (2024) Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue. Cell Discov. 10:64. https://doi.org/10.1038/s41421-024-00681-0

This is a publication in which we used scRNAseq, spatial transcriptomics, and machine learning algorithms to define the biology of Tfh cells induced following type-1 and type-2 immune responses. We identified a population of Gzmk+ Tfh cells that are induced in type-1 responses.

Malato J, Ribeiro RM, Leite PP, Casaca P, Antunes C, Fonseca VR, Gomes MC, Graca L. (2023) Stability of hybrid versus vaccine immunity against BA.5 infection over 8 months. Lancet Infect Dis. 23:148–150.

We calculated the decline in the rate of protection against SARS-CoV-2 infection (immune waning) following hybrid immunity using national registries and mathematical models. It received broad media coverage, including a commentary in Nature46, and influenced the timing of vaccine boosters in the EU (see also Graca et al 2023. Nature Immunol. 10.1038/s41590-034-01518-w)

Malato J, Ribeiro RM, Leite PP, Casaca P, Fernandes E, Antunes C, Fonseca VR, Gomes MC, Graca L. (2022) Risk of BA.5 infection in individuals exposed to prior SARS-CoV-2 variants. N Engl J Med.https://doi.org/10.1056/NEJMc2209479

In this publication, we quantified the protection afforded by Omicron BA.1 infection in vaccinated individuals against a subsequent infection with Omicron BA.5. EMA used this information to support the decision to authorize BA.1-based vaccines when the BA.5 subvariant was already dominant. There was very broad media coverage and impact (Altmetric: 99% percentile, 95% within NEJM).

Kumar S, Fonseca VR, Ribeiro F, Basto AP, Agua-Doce A, Monteiro M, Miragaia RJ, Gomes T, Piaggio E, Segura E, Gama-Carvalho M, Teichmann SA, Graca L. (2021) Developmental bifurcation of human T follicular regulatory cells. Sci Immunol. 6:eabd8411.

The differentiation of human Tfh and Tfr cells was hard to study, as in vitro experimental systems (especially before tonsil organoids were established) had significant limitations. We overcame this challenge by examining the differentiation of Tfh and Tfr cells in vivo using scRNAseq and newly established computational methods. We defined the sequence of molecular events that Tfh and Tfr cells follow as they differentiate within human secondary lymphoid tissue.

Deng J, Wei Y, Fonseca VR, Graca L, Yu D. (2019) Follicular helper and follicular regulatory T cells in autoimmune rheumatic diseases: phenotype, pathogenesis and targeted immunotherapies. Nat Rev Rheumatol. 15:475. (joint senior/corresponding authors)

A review written in collaboration with Di Yu (Melbourne), where we discussed how Tfh and Tfr cell populations can be key cellular regulators of autoimmune rheumatic diseases, including SjD.

Fonseca VR, Romão VC, Agua-Doce A, Santos M, López-Presa D, Ferreiras AC, Fonseca JE, Graca L. (2018) The ratio of blood T follicular regulatory cells to T follicular helper cells marks ectopic lymphoid structure formation while activated follicular helper T cells indicate disease activity in primary Sjögren’s Syndrome. Arthritis Rheumatol. 70:774–784.

This publication established that circulating Tfh and Tfr subsets could discriminate patients with SjD with different clinical characteristics. Among those, PD-1+ICOS+ Tfh cells in the peripheral blood correlated closely with disease activity. This paper was highlighted in Nat Rev Rheumatol and Arthritis Rheumatol44,45.

Fonseca VR, Agua-Doce A, Maceiras AR, Pierson W, Ribeiro F, Romão VC, Pires AR, Silva SL, Fonseca JE, Sousa AE, Linterman MA, Graca L. (2017) Human blood CXCR5+Foxp3+ T cells are indicators of ongoing humoral activity not fully licensed with suppressive function. Sci Immunol. 2:eaan1487.

Landmark publication establishing the biology of human circulating Tfr cells, and their role in SjD. It involved studying clinical samples from SjD patients, pediatric tonsils with paired blood, a cohort of influenza-vaccinated health-care workers, and BTK-deficient individuals lacking B cells (to establish mechanistic relations). Commentary in Nature Immunol41.

Maceiras R, Almeida SCP, Mariotti-Ferrandiz E, Chaara W, Jebbawi F, Six A, Hori S, Klatzmann D, Faro J, Graca L. (2017) T follicular helper and T follicular regulatory cells from the same germinal centers have different TCR-specificity. Nat Commun. 8:15067.

Important publication in establishing that, within the same GC, Tfh and Tfr cells have a different TCR repertoire: while the TCR of Tfh cells is directed to the immunizing antigen, Tfr cells have TCRs related to the Treg cell repertoire and directed to autoantigens. This finding supports a division of labour: while Tfh cells provide help towards the development of high-affinity B cells, Tfr cells prevent the emergence of autoreactivity. More recently, additional Tfr populations differentiating from Tfh were found (see Graca et al 2023, Sci Immunol 8:eadg7526).

Oliveira VG, Agua-Doce A, Curotto de Lafaille MA, Lafaille JJ, Graca L. (2013) Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10. Blood121:3936–3945.

This publication led to the realization that adjuvants are important for boosting immune responses but can also be critical for recruiting distinct immune-tolerance mechanisms. It influenced subsequent research (in my group and elsewhere) on the impact of adjuvants on Tfh, Tfr, and Treg polarization and immune regulation.

Wollenberg I, Agua-Doce A, Hernández A, Almeida C, Oliveira VG, Faro J, Graca L. (2011) Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J Immunol. 187:4553–4560.

This publication reports the discovery of Tfr cells as key regulators of the GC response. It has influenced my research direction since then.

A complete list of publications can be found here.

Luis Graca chairs the National Immunization Technical Advisory Committee for seasonal vaccination against influenza and COVID-19.

The laboratory has a long standing tradition in hosting visual artists to explore the intersection of art and biomedical sciences (with an emphasis on art and immunology), with outcomes exhibited internationally in cities such as Linz, New York, Beijing, Berlin, Dublin, Toronto, St. Petersburg, Amsterdam, and Lisbon.

Marta de Menezes (https://martademenezes.com) is Associate Artist at the laboratory, and curates the art program.

Selected Artists and Projects:

• Marta de Menezes – projects on immunity: https://martademenezes.com/art/immunity/
• Nigel Helyer: https://www.sonicobjects.com
• Andrew Carnie: https://www.andrewcarnie.uk
• Whitefeather Hunter: https://www.whitefeatherhunter.ca
• Guy Ben-Ary: https://guybenary.com
• Rudolfo Quintas: https://cultivamoscultura.com/2024/11/11/residency-by-rudolfo-quintas-8-to-22-november/
• Oron Catts and Ionat Zurr: https://cultivamoscultura.com/2023/12/19/residency-by-ionat-zurr-oron-catts-december-2023/
• Untammed complexity: Art exhibition of projects from the lab at the European Congress of Immunology in Dublin (2024): https://cultivamoscultura.com/2024/08/28/enlightten-untamed-complexity-31-aug-2-sept-dublin-2024/

ORCID: https://orcid.org/0000-0001-6935-8500