Abstract
CD4+ T cells integrate well-defined signals from the T-cell receptor (TCR) (signal 1) and a host of costimulatory molecules (signal 2) to initiate clonal expansion and differentiation into diverse functional T helper (Th) subsets. However, our ability to guide the expansion of context-appropriate Th subsets by deploying these signals in vaccination remains limited. Using cell-based vaccines, we selectively amplified signal 1 by exclusive presentation of an optimized peptide:MHC II (pMHC II) complex in the absence of classic costimulation. Contrary to expectations, amplified signal 1 alone was strongly immunogenic and selectively expanded high-affinity TCR clonotypes, despite delivering intense TCR signals. In contrast to natural infection or standard vaccines, amplified signal 1, presented by a variety of professional and nonprofessional antigen-presenting cells (APCs), induced exclusively polyfunctional Th1 effector and memory cells, which protected against retroviral infection and tumor challenge, and expanded tumor-reactive CD4+ T cells otherwise rendered unresponsive in tumor-bearing hosts. Together, our findings uncover a default Th1 response to ample signal 1 and offer a means to selectively prime such protective responses by vaccination.
Highlights
Adaptive immunity and immunological memory rely on clonal expansion and differentiation of T cells bearing appropriate T-cell receptors (TCRs), which recognize cognate peptide:MHC complexes on the surface of antigen-presenting cells (APCs)
To determine whether env-reactive CD4+ T cells prefer an optimum peptide length, we tested the ability of nested env peptides, ranging in length from 11 to 35 amino acid residues (Fig. S1a), to stimulate EVα2 TCRαβ-transgenic CD4+ T cells.[33]
As with the parental EF4.1 TCRβ-transgenic CD4+ T cells with the same reactivity,[34] EVα2 T cells responded to these peptides according to the peptide dose and length, with the strongest upregulation of early activation markers, as well as commitment to proliferation, seen in the response to the highest doses of the 15-mer or the 20-mer (Fig. S1b)
Summary
Adaptive immunity and immunological memory rely on clonal expansion and differentiation of T cells bearing appropriate T-cell receptors (TCRs), which recognize cognate peptide:MHC (pMHC) complexes on the surface of antigen-presenting cells (APCs). In addition to initiating clonal expansion, the overall strength of TCR signaling received by CD4+ T cells influences functional differentiation into one or more distinguishable T helper (Th), follicular helper (Tfh) and regulatory T (Treg) cell subsets.[5,6,7,8,9,10] Strong TCR signals are linked with Tfh differentiation, this is not universally observed.[11,12,13,14] Th differentiation is guided by a multitude of T-cell-extrinsic factors that can override the influence of TCR signal strength to ensure appropriate Th subset development.[5,6,7,8,9] This is a critical adaptation that allows CD4+ T cells of similar affinities to adopt distinct Th profiles, according to the immune context. Despite detailed knowledge of the factors and transcriptional programs underpinning Th polarization,[5,6,7,8,9] the ability to direct appropriate Th subset development is not yet fully developed in current vaccination or immunotherapy regimens
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