Immunodeficiencies

We use our expertise to study T cells in patients with chronic immunodeficiency in collaboration with medical doctors of the Centre of Chronic Immunodeficiency, CCI, where Wolfgang Schamel is professor. Here, three examples are given:

Together with Prof. Klaus Schwarz we have analysed the activity of a mutant of the kinase LCK that phosphorylates the TCR. This mutant is found in a patient with immunodeficiency (Lui et al, 2024).

Since long time we cooperate with Prof. Stephan Ehl to study the activation of T cells with mutations in signalling proteins involved in TCR signalling (Hauck et al, 2015; Hillen et al, 2015; Fuchs et al, 2012; Maul-Pavicic et al, 2011).

We have collaborated with the group of Prof. Klaus Warnatz to analyse the T cells of the first patient with a mutation in the adaptor protein LAT that is critical for signal transmission initiated by the TCR (Keller et al, 2016).

We work on human CD3g- and CD3d-deficiencies in cooperation with Prof. Jose-Ramon Regueiro from Madrid (Siegers et al, 2007; Rossi et al, 2008; Gil et al, 2011; Garcillán et al, 2022). In addition to human patients we also use a humanized mouse strain as a model system that we have generated.

References

Lui VG, Hoenig M, Cabrera-Martinez B, Baxter RM, Garcia-Perez JE, Bailey O, Acharya A, Lundquist K, Capera J, Matusewicz P, et al (2024) A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation. J Exp Med 221

Garcillán B, Megino RF, Herrero-Alonso M, Guardo AC, Perez-Flores V, Juraske C, Idstein V, Martin-Fernandez JM, Geisler C, Schamel WWA, et al (2022) The role of the different CD3γ domains in TCR expression and signaling. Front Immunol 13: 978658

Keller B, Zaidman I, Yousefi OS, Hershkovitz D, Stein J, Unger S, Schachtrup K, Sigvardsson M, Kuperman AA, Shaag A, et al (2016) Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT. J Exp Med 213: 1185–99

Hillen KM, Gather R, Enders A, Pircher H, Aichele P, Fisch P, Blumenthal B, Schamel WW, Straub T, Goodnow CC, et al (2015) T cell expansion is the limiting factor of virus control in mice with attenuated TCR signaling: implications for human immunodeficiency. J Immunol 194: 2725–34

Hauck F, Blumenthal B, Fuchs S, Lenoir C, Martin E, Speckmann C, Vraetz T, Mannhardt-Laakmann W, Lambert N, Gil M, et al (2015) SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling. Clin Immunol 161: 103–9

Fuchs S, Rensing-Ehl A, Speckmann C, Bengsch B, Schmitt-Graeff A, Bondzio I, Maul-Pavicic A, Bass T, Vraetz T, Strahm B, et al (2012) Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency. J Immunol 188: 1523–33

Gil J, Busto EM, Garcillán B, Chean C, García-Rodríguez MC, Díaz-Alderete A, Navarro J, Reiné J, Mencía A, Gurbindo D, et al (2011) A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a Tαβ-Tγδ+B+NK+ human SCID. J Clin Invest 121: 3872–6

Maul-Pavicic A, Chiang SCC, Rensing-Ehl A, Jessen B, Fauriat C, Wood SM, Sjöqvist S, Hufnagel M, Schulze I, Bass T, et al (2011) ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Proc Natl Acad Sci U S A 108: 3324–9

Rossi NE, Reiné J, Pineda-Lezamit M, Pulgar M, Meza NW, Swamy M, Risueno R, Schamel WWA, Bonay P, Fernández-Malavé E, et al (2008) Differential antibody binding to the surface alphabetaTCR.CD3 complex of CD4+ and CD8+ T lymphocytes is conserved in mammals and associated with differential glycosylation. Int Immunol 20: 1247–58

Siegers GM, Swamy M, Fernández-Malavé E, Minguet S, Rathmann S, Guardo AC, Pérez-Flores V, Regueiro JR, Alarcón B, Fisch P, et al (2007) Different composition of the human and the mouse gammadelta T cell receptor explains different phenotypes of CD3gamma and CD3delta immunodeficiencies. J Exp Med 204: 2537–44