Impact of Regulated Secretion on Antiparasitic CD8 T Cell Responses

Abstract

Summary CD8 T cells play a key role in defense against the intracellular parasite Toxoplasma but why certain CD8 responses are more potent than others is not well understood. Here, we describe a parasite antigen ROP5 that elicits a modest CD8 T cell response in genetically susceptible mice. ROP5 is secreted via parasite organelles termed rhoptries that are injected directly into host cells during invasion, whereas the protective, dense granule antigen, GRA6, is constitutively secreted into the parasitophorous vacuole. Transgenic parasites in which the ROP5 antigenic epitope was targeted for secretion through dense granules led to enhanced CD8 T cell responses, whereas targeting the GRA6 epitope to rhoptries led to reduced CD8 responses. CD8 T cell responses to the dense granule-targeted ROP5 epitope resulted in reduced parasite load in the brain. These data suggest that the mode of secretion impacts the efficacy of parasite-specific CD8 T cell responses.

Continuous Effector CD8 + T Cell Production in a Controlled Persistent Infection Is Sustained by a Proliferative Intermediate Population

“…We compared the anti-GRA6:L d response to subdominant CD8+ T cell responses specific for peptides derived from parasite proteins GRA4 and ROP5 (Frickel et al, 2008; Grover et al, 2014) using F1 (H-2 bxd ) mice orally infected with tissue cysts generated from the type II T. gondii strain, Prugniaud (Pru). Infected cells in both the draining mesenteric lymph nodes (MLN) and spleen peaked at 7 days after infection and were undetectable by day 21.…”

“…With regard to the latter, it is intriguing to note that MHC-I variants associated with HIV elite control, and the MHC-I molecule L d that presents the immunodominant parasite antigen GRA6, share structural features including atypical peptide binding properties (International et al, 2010; Kosmrlj et al, 2010; Narayanan and Kranz, 2013). For the GRA6 antigen, a number of other factors contribute to efficient antigen presentation, including the secretion pattern of the antigenic protein within the invaded host cell, and the location of the epitope within the precursor protein (Feliu et al, 2013; Grover et al, 2014; Lopez et al, 2015). Thus, both features of a particular antigenic protein and presentation by an atypical MHC-I molecule may contribute to an unusually protective CD8+ T cell response.…”

“…infected with the type II Prugniuad-tomato-OVA strain (Pru)(Chtanova et al, 2008) or the type III CEP strain (Grover et al, 2014) T. gondii . Detailed protocols for infection and flow cytometric staining of cell suspensions from the spleen, lymph nodes, and brains of infected mice are described in Supplemental Experimental Procedures .…”

Persistence of Toxoplasma gondii in the central nervous system: a fine‐tuned balance between the parasite, the brain and the immune system

“…Although robust endogenous responses are mounted against third‐party model antigens, their impact on the course of chronic toxoplasmosis seems rather modest . Furthermore, immunization with the naturally processed 28 m and ROP5 antigens conferred no or only partial protection .…”

“…This seminal finding was corroborated by further work with the ovalbumin (OVA) model antigen, which was recognized by T-cell receptor-transgenic CD8 + (11) and CD4 + (12) T cells. Moreover, by the identification of 6 natural antigens eliciting T-cell responses during infection, which all contain signal peptides (13)(14)(15)(16)(17). Although robust endogenous responses are mounted against third-party model antigens, their impact on the course of chronic toxoplasmosis seems rather modest (10,18).…”