# Severe malaria enforces short-lived effector cell differentiation but does not prevent effective secondary responses by memory CD8 T cells

## TL;DR

Malaria causes CD8 T cells to become short-lived, but the few memory cells that remain can still protect against future infections.

## Contribution

The study reveals that Plasmodium infection uniquely programs CD8 T cells and shows that limited memory does not hinder host protection.

## Key findings

- PbA infection biases CD8 T cells toward a short-lived effector cell phenotype with reduced memory precursor formation.
- PbA-induced inflammation, including IFNγ, contributes to the effector cell bias in CD8 T cells.
- Despite low memory T cell numbers after PbA, they can robustly expand and protect during secondary infections.

## Abstract

Parasitic infections are a major worldwide health burden, yet most studies of CD8 T cell differentiation focus on acute viral and bacterial infections. To understand effector and memory CD8 T cell responses during erythrocytic malaria infection in mice, we utilized transgenic OT-I T cells and compared CD8 T cell responses between infection with OVA-expressing strains of Listeria monocytogenes (Lm) and Plasmodium berghei ANKA (PbA). We find that CD8 T cells expand vigorously during both infections. However, in contrast to Lm infection, PbA infection induces T cells that are heavily biased toward an IL-7Ra-deficient and KLRG1+ short-lived effector cell (SLEC) phenotype at the expense of memory precursor effector cell (MPECs) formation. PbA-induced inflammation, including IFNγ, is partially responsible for this outcome. Following treatment with antimalarial drugs and T cell contraction, PbA-primed memory T cells are rarely found in the blood and peripheral tissues but do maintain a low presence in the spleen and bone marrow. Despite these poor numbers, PbA memory T cells robustly expand upon vaccination or viral infection, control pathogen burden, and form secondary memory pools. Thus, despite PbA enforced SLEC formation and limited memory, effective secondary responses can still proceed.

Following pathogen infection, CD8 T cells eliminate infected cells and form diverse pools of memory T cells that are critical to prevent reinfection. Both the timing and intensity of inflammatory signals present during T cell activation play a major role in the subsequent phenotype of responding CD8 T cells. Infection with Plasmodium, the causative agent of malaria, is a major worldwide health burden, but the response of CD8 T cells to this infection is not completely understood. Infection can result in a highly inflammatory and systemic infection of the blood. Using mouse models of infection, we asked how Plasmodium infection impacts responding CD8 T cells and compared this response to that of a well-studied bacterial infection, Listeria monocytogenes. We find that Plasmodium programs a unique phenotype among effector CD8 T cells that is at least partially caused by malaria-induced inflammation. Additionally, we find that after infection is resolved through antimalarial drug administration, CD8 T cells form substantially diminished memory pools. Despite this apparent deficiency, the few memory CD8 T cells that do persist are capable of expansion and protection following secondary infection. Our study highlights the unique impact of Plasmodium infection on CD8 T cells, and that seemingly poor memory does not necessarily impede host protection.