Do Memory CD4 T Cells Keep Their Cell-Type Programming: Plasticity versus Fate Commitment?

Crotty, Shane

doi:10.1101/cshperspect.a032102

Cited by 50 publications

(18 citation statements)

References 52 publications

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“…For example, standard panels are often Th1-skewed, predominantly staining for IFNγ and IL-2 [ 1 , 2 ]. CD4 T cell responses are remarkably heterogeneous, and thus detection of antigen-specific CD4 T cells by one or more cytokines produced is likely to significantly underestimate the size of the total antigen-specific response [ 3 , 4 ]. Furthermore, ICS and ELISpot assays only detect cells that produce cytokine above a certain threshold, although cells that produce cytokines below this threshold are likely to be biologically relevant.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells

et al. 2017

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The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods. We have developed assays for the highly sensitive detection of such cells by measuring the upregulation of surface activation induced markers (AIM). Here, we compare two such assays based on concurrent expression of CD69 plus CD40L (CD154) or expression of OX40 plus CD25, and we develop additional AIM assays based on OX40 plus PD-L1 or 4-1BB. We compare the relative sensitivity of these assays for detection of vaccine and natural infection-induced CD4 T cell responses and show that these assays identify distinct, but overlapping populations of antigen-specific CD4 T cells, a subpopulation of which can also be detected on the basis of cytokine synthesis. Bystander activation had minimal effect on AIM markers. However, some T regulatory cells upregulate CD25 upon antigen stimulation. We therefore validated AIM assays designed to exclude most T regulatory cells, for both human and non-human primate (NHP, Macaca mulatta) studies. Overall, through head-to-head comparisons and methodological improvements, we show that AIM assays represent a sensitive and valuable method for the detection of antigen-specific CD4 T cells.

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Section: Introductionmentioning

confidence: 99%

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells

et al. 2017

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“…Instead, the env-reactive CD4 + T cells with the highest TCR signal, assessed by both the activity of the Nur77-GFP reporter and the degree of surface TCR downregulation, appeared inhibited in their commitment to either the Th1 or Tfh subsets. These cells, which we refer to as uncommitted Th0 cells ( 44 ), also strongly correlated with co-expression of the inhibitory receptors PD-1 and LAG3.…”

Section: Discussionmentioning

confidence: 94%

“…Notable, however, were the relative paucity (~10%) of env-reactive EF4.1 CD4 + T cells with a Th1 phenotype (PSGL1 + PD-1 + SLAM + CXCR5 − Bcl6 − Ly6C − ) ( 43 ) and the presence of a sizable population (~35%) of cells that lacked markers of Tfh or Th1 commitment (PSGL1 − SLAM − CXCR5 − ) (Figures 1 A,B). The latter population, referred here as Th0 to denote their uncommitted state ( 44 ), retained TCF-1 expression and expressed low levels of Bcl6 (Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…Seemingly uncommitted Th0 cells are not typically observed in acute viral infections ( 44 ), but a similar population lacking either Th1 or Tfh characteristics has been described in CD4 + T cells primed during the chronic phase of LCMV Cl13 infection ( 18 ). In that model, the emergence of Th0 cells was linked to an initial defect in effector differentiation, indirectly caused by chronic IFN type I production ( 18 ).…”

Section: Discussionmentioning

confidence: 97%

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Correlates of Follicular Helper Bias in the CD4 T Cell Response to a Retroviral Antigen

2018

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CD4+ T cell differentiation is influenced by a plethora of intrinsic and extrinsic factors, providing the immune system with the ability to tailor its response according to specific stimuli. Indeed, different classes of pathogens may induce a distinct balance of CD4+ T cell differentiation programmes. Here, we report an uncommonly strong bias toward follicular helper (Tfh) differentiation of CD4+ T cells reactive with a retroviral envelope glycoprotein model antigen, presented in its natural context during retroviral infection. Conversely, the response to the same antigen, presented in different immunization regimens, elicited a response typically balanced between Tfh and T helper 1 cells. Comprehensive quantitation of variables known to influence Tfh differentiation revealed the closest correlation with the strength of T cell receptor (TCR) signaling, leading to PD-1 expression, but not with surface TCR downregulation, irrespective of TCR clonotypic avidity. In contrast, strong TCR signaling leading to TCR downregulation and induction of LAG3 expression in high TCR avidity clonotypes restrained CD4+ T cell commitment and further differentiation. Finally, stunted Th1 differentiation, correlating with limited IL-2 availability in retroviral infection, provided permissive conditions for Tfh development, suggesting that Tfh differentiation is the default program of envelope-reactive CD4+ T cells.

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“…Expression of these transcription factors during the differentiation of naive CD4 T cells is thought, largely, to imprint particular functional profiles into memory CD4 T cells, such that reexposure to the same antigen would result in appropriate effector functions being performed. Functional plasticity can exist in some circumstances, however, and CD4 T cells differentiated toward one particular functionality can become hyperfunctional or can fluctuate toward a different functional lineage (2)(3)(4). For example, IL-17-and IL-22-producing memory Th17 cells can, under some circumstances, produce the Th1 effector cytokine IFN-␥, with such coexpression being associated with autoimmunity (5).…”

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confidence: 99%

Simian Immunodeficiency Virus Infects Functionally Polarized Memory CD4 T Cells Equivalently In Vivo

Lai

Starke

Flynn

et al. 2019

J Virol

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Among the numerous immunological abnormalities observed in chronically human immunodeficiency virus (HIV)-infected individuals, perturbations in memory CD4 T cells are thought to contribute specifically to disease pathogenesis. Among these, functional imbalances in the frequencies of T regulatory cells (Tregs) and interleukin 17 (IL-17)/IL-22-producing Th cells (Th17/Th22) from mucosal sites and T follicular helper (Tfh) cells in lymph nodes are thought to facilitate specific aspects of disease pathogenesis. However, while preferential infection of Tfh cells is widely thought to create an important viral reservoir in an immunologically privileged site in vivo, whether immunological perturbations among memory CD4 T cell populations are attributable to their relative infectivity by the virus in vivo is unclear.Here we studied peripheral blood and lymphoid tissues from antiretroviral (ARV)treated and ARV-naive Asian macaques and isolated functionally defined populations of memory CD4 T cells. We then assessed the degree to which these populations were infected by simian immunodeficiency virus (SIV) in vivo, to determine whether particular functionally identified populations of memory CD4 T cells were preferentially infected by the virus. We found that SIV did not preferentially infect Th17 cells, compared to Th1 cells, Th2 cells, or Tregs. Moreover, Th17 cells contributed proportionately to the total pool of infected cells. Taken together, our data suggest that, although Tfh cells are more prone to harbor viral DNA, other functionally polarized cells are equally infected by the virus in vivo and Th17 cells are not preferentially infected. IMPORTANCE Functional perturbations of memory CD4 T cells have been suggested to underlie important aspects of HIV disease progression. However, the mechanisms underlying these perturbations remain unclear. Using a nonhuman primate model of HIV, we show that SIV infects functionally defined populations of memory CD4 T cells equally in different anatomic sites. Thus, preferential infection by the virus is unlikely to cause functional perturbations.

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Do Memory CD4 T Cells Keep Their Cell-Type Programming: Plasticity versus Fate Commitment?

Cited by 50 publications

References 52 publications

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells

Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells

Correlates of Follicular Helper Bias in the CD4 T Cell Response to a Retroviral Antigen

Simian Immunodeficiency Virus Infects Functionally Polarized Memory CD4 T Cells Equivalently In Vivo

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