Cutting Edge: Virus-Specific CD4+ Memory T Cells in Nonlymphoid Tissues Express a Highly Activated Phenotype

Abstract

Recent studies have shown that CD4+ memory T cells persist in nonlymphoid organs following infections. However, the development and phenotype of these peripheral memory cells are poorly defined. In this study, multimerized MHC-Ig fusion proteins, with a covalently attached peptide sequence from the Sendai virus hemagglutinin/neuraminidase gene, have been used to identify virus-specific CD4+ T cells during Sendai virus infection and the establishment of peripheral CD4+ memory populations in the lungs. We show declining frequencies of virus-specific CD4+ T cells in the lungs over the course of ∼3 mo after infection. Like peripheral CD8+ T cells, the CD4+ have an acutely activated phenotype, suggesting that a high level of differentiation is required to reach the airways and persist as memory cells. Differences in CD25 and CD11a expression indicate that the CD4+ cells from the lung airways and parenchyma are distinct memory populations.

CD4 T cell responses to influenza infection

“…The CD4 memory response to Sendai virus is also heterogeneous [42]. Phenotypic markers such as CD43 and CD11a are differentially expressed on tetramer positive cells in the lung parenchyma compared to the airways and tet + cells in the lung demonstrate a highly activated phenotype compared to cells in the lymphoid organs [42]. Taken together, these data suggest that there are multiple, phenotypically diverse subsets of memory CD4 cells that are likely to function differently.…”

“…The generation of heterogeneous memory subsets in different organs suggests that functional CD4 memory could be different based on distinct anatomical localization. The CD4 memory response to Sendai virus is also heterogeneous [42]. Phenotypic markers such as CD43 and CD11a are differentially expressed on tetramer positive cells in the lung parenchyma compared to the airways and tet + cells in the lung demonstrate a highly activated phenotype compared to cells in the lymphoid organs [42].…”

“…Importantly, this technology has provided insight to the differences in expansion, contraction and memory generation between virus-specific CD8 and CD4 responses. For both LCMV [41] and Sendai infection [42], it has been observed that the CD8 expansion or burst size is greater than the CD4 expansion phase. Virus-specific CD4 cells contract with different kinetics than CD8 cells and the frequency of CD4 cells detected in the memory pool is much lower (1 in 500) than the frequency of CD8 cells (1 in 12) [41].…”

“…It has been demonstrated, using multimers, that the contraction phase in the CD4 compartment is more pronounced than in the CD8 population, leading to a decline in CD4 cell numbers in the memory phase in LCMV [41] and Sendai infection [42]. Tracking CD4 cells into the memory phase after influenza infection has been technically difficult due to the low numbers of CD4 cells that persist into memory, and the availability of reagents to detect low frequencies of cells.…”

“…T cell receptors from two of these clones have been used to generate TCR Tg mice that recognize either HA 110-120 [48] or HA 126-138 [49]. Despite the availability of some reagents, the low frequency of CD4 cells and low affinity of class II multimers for peptide makes detection of the primary response difficult without first priming in the presence of peptide and adjuvant [42].…”