A new therapeutic strategy for malaria: targeting T cell exhaustion

Abstract

Boosting immune responses during malaria remains a challenge. Overcoming T cell exhaustion by blocking coinhibitory receptors offers a promising lead.

Figure 1

T cell exhaustion. (a) Exhausted CD4⁺ T cells in malaria upregulate PD-1 and LAG-3. Combined blockade of PD-L1 and LAG-3 allows more CD4⁺ T cell activation and the provision of help by CD4⁺ T cells for B cell antibody production. LAG-3 is a transmembrane protein composed of four immunoglobulin domains with a structure similar to that of the coreceptor CD4 but a higher affinity for MHC class II. The first immunoglobulin domain contains an extra loop region important for binding to MHC class II. The cytoplasmic domain contains a KIEELE motif that is required for LAG-3-mediated immunoinhibition. PD-1 contains a single immunoglobulin V domain and two tyrosine-phosphorylation motifs in its cytoplasmic domain that engage the tyrosine phosphatase SHP-2. ITSM, immunoreceptor tyrosine-based switch motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; CD3, signaling complex of the TCR; APC, antigen-presenting cell. (b) Coinhibitory pathways. Exhausted T cells can express multiple inhibitory receptors, which are called `coinhibitory' because they modify the outcome of a T cell antigen receptor signal and limit the population expansion, functional activity and survival of T cells. CD4⁺ T cells and CD8⁺ T cells express overlapping but distinct coinhibitory receptors. During malaria infection, CD244 and CD160 are expressed on exhausted CD8⁺ T cells but not on exhausted CD4⁺ T cells. PtdSer, phosphatidylserine.