The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite
this critical role, it is not known whether CD28 has functions in maintaining T cell responses
following activation. To determine the role for CD28 after T cell priming, we generated a strain
of mice where CD28 is removed from CD4+ T cells after priming. We show that continued CD28
expression is important for effector CD4+ T cells following infection; maintained CD28 is required
for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular
helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium
Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28
persistence is required for helper T cell polarization in response to infection, describing a novel
function for CD28 that is distinct from its role in T cell priming.