CD5 as immunomodulatory agent in experimental models of fungal infection

Abstract

CD5 is a scavenger receptor mainly expressed on lymphoid (T and B1a) cells but also on some minor myeloid (Mϕ and DCs) cell subsets. It is long known to negatively modulate differentiation and activation signals mediated by the clonotypic antigen specific receptor complexes of T (TCR) and B1a (BCR) lymphocytes, both being an identity hallmark of the adaptive immune system (Burgueño‐Bucio et al., 2019). Recently, several reports have also shown its ability to recognise and signal the presence of PAMPs of fungal, viral and parasitic origin (Consuegra-Fernández et al., 2015; Burgueño‐Bucio et al., 2019), which is a formal trait of PRRs expressed by the innate immune system’s components (Salazar and Brown, 2018). In consequence, CD5 can be considered as a relevant immunomodulatory receptor at the interphase between the innate and adaptive immune responses. IFIs have emerged in recent decades as a significant health problem associated with high morbidity, mortality, and economic burden (Klingspor et al., 2015). Nowadays, only a few antifungal drugs are available and their use is limited by their associated side effects, making necessary the development of new alternative or complementary therapeutic strategies (Nami et al., 2019). The discovery by our group that CD5 binds with relative high affinity to and signal the presence of β-glucans (Vera et al., 2009) -a constitutive and highly conserved component of fungal cell walls -motivated our interest on exploring the CD5’s physiological function and/or therapeutic potential in IFIs. In our view, the study of soluble and/or membrane-bound immune receptors involved in antifungal immunity, as it may be the case of CD5, could provide an important source of functional information to be translated into such a novel therapeutic approaches.

Based on the above mentioned premises, the specific objectives of this thesis have been the following: - To study the influence of the mouse genetic background on fungal infection by analyzing the antifungal immune response of the inbred (C57) and outbred (CD1) mouse strains most widely used in basic and pharma-industry research. - To study the influence of membrane-bound CD5 on fungal infection by analyzing the antifungal immune response of mice genetically deficient for CD5 (cd5-/-). - To study the therapeutic potential of soluble human CD5 administration (alone or in combination) in experimental models of fungal infection. - To study the therapeutic potential of CD5-based adoptive cell transfer strategies by analysing the influence of immune cells transduced with membrane-bound chimerical CD5 receptors in pre-clinical models of fungal infection.