Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection

AbstractThe ability of HIV to avoid recognition by humoral and cellular immunity (viral escape) is well documented but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection as compared to the chronic infection. With the help of simple mathematical models the rate of HIV escape was estimated and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. These conclusions, however, were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a parametric resampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in the chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses.

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Role of the NF-κB transcription factor c-Rel in the generation of CD8+ T-cell responses to Toxoplasma gondii

International Immunology ◽

10.1093/intimm/dxq439 ◽

2010 ◽

Vol 22 (11) ◽

pp. 851-861 ◽

Cited By ~ 10

Author(s):

Kimberly A. Jordan ◽

Christopher D. Dupont ◽

Elia D. Tait ◽

Hsiou-Chi Liou ◽

Christopher A. Hunter

Keyword(s):

Transcription Factor ◽

T Cell ◽

Toxoplasma Gondii ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Factor C

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Faculty Opinions recommendation of Magnitude and complexity of rectal mucosa HIV-1-specific CD8+ T-cell responses during chronic infection reflect clinical status.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1135913.593010 ◽

2008 ◽

Author(s):

Holden Maecker

Keyword(s):

T Cell ◽

Chronic Infection ◽

Clinical Status ◽

Rectal Mucosa ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Hiv 1

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Delayed Expression of PD-1 and TIGIT on HIV-Specific CD8 T Cells in Untreated HLA-B*57:01 Individuals Followed from Early Infection

Journal of Virology ◽

10.1128/jvi.02128-19 ◽

2020 ◽

Vol 94 (14) ◽

Cited By ~ 1

Author(s):

Lydia Scharf ◽

Johanna Tauriainen ◽

Marcus Buggert ◽

Wendy Hartogensis ◽

David J. Nolan ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Hla Class I ◽

Cd8 T Cell ◽

Receptor Expression ◽

T Cell Exhaustion ◽

Inhibitory Receptor ◽

Cell Exhaustion ◽

Cell Responses ◽

Immunomodulatory Therapies

ABSTRACT While the relationship of protective human leukocyte antigen (HLA) class I alleles and HIV progression is well defined, the interaction of HLA-mediated protection and CD8 T-cell exhaustion is less well characterized. To gain insight into the influence of HLA-B*57:01 on the deterioration of CD8 T-cell responses during HIV infection in the absence of antiretroviral treatment, we compared HLA-B*57:01-restricted HIV-specific CD8 T-cell responses to responses restricted by other HLA class I alleles longitudinally after control of peak viremia. Detailed characterization of polyfunctionality, differentiation phenotypes, transcription factor, and inhibitory receptor expression revealed progression of CD8 T-cell exhaustion over the course of the infection in both patient groups. However, early effects on the phenotype of the total CD8 T-cell population were apparent only in HLA-B*57-negative patients. The HLA-B*57:01-restricted, HIV epitope-specific CD8 T-cell responses showed beneficial functional patterns and significantly lower frequencies of inhibitory receptor expression, i.e., PD-1 and coexpression of PD-1 and TIGIT, within the first year of infection. Coexpression of PD-1 and TIGIT was correlated with clinical markers of disease progression and declining percentages of the T-bethi Eomesdim CD8 T-cell population. In accordance with clinical and immunological deterioration in the HLA-B*57:01 group, the difference in PD-1 and TIGIT receptor expression did not persist to later stages of the disease. IMPORTANCE Given the synergistic nature of TIGIT and PD-1, the coexpression of those inhibitory receptors should be considered when evaluating T-cell pathogenesis, developing immunomodulatory therapies or vaccines for HIV, and when using immunotherapy or vaccination for other causes in HIV-infected patients. HIV-mediated T-cell exhaustion influences the patient´s disease progression, immune system and subsequently non-AIDS complications, and efficacy of vaccinations against other pathogens. Consequently, the possibilities of interfering with exhaustion are numerous. Expanding the use of immunomodulatory therapies to include HIV treatment depends on information about possible targets and their role in the deterioration of the immune system. Furthermore, the rise of immunotherapies against cancer and elevated cancer incidence in HIV-infected patients together increase the need for detailed knowledge of T-cell exhaustion and possible interactions. A broader approach to counteract immune exhaustion to alleviate complications and improve efficacy of other vaccines also promises to increase patients’ health and quality of life.

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Defining Kinetic Properties of HIV-Specific CD8+ T-cell Responses in Acute Infection

10.20944/preprints201901.0065.v1 ◽

2019 ◽

Author(s):

Yiding Yang ◽

Vitaly V. Ganusov

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

Cd8 T Cells ◽

Chronic Infection ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Responses ◽

Average Viral Load

Multiple lines of evidence indicate that CD8$^+$ T cells are important in the control of HIV-1 (HIV) replication. However, CD8$^+$ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8$^+$ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8$^+$ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8$^+$ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8$^+$ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8$^+$ T cells in the chronic infection. The breadth of HIV-specific CD8$^+$ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8$^+$ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8$^+$ T-cell responses and the presence of intra- and interclonal competition between multiple CD8$^+$ T-cell responses; such competition may limit the magnitude of CD8$^+$ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8$^+$ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

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An Unusual MHC Molecule Generates Protective CD8+ T Cell Responses to Chronic Infection

Frontiers in Immunology ◽

10.3389/fimmu.2020.01464 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alexandra Tsitsiklis ◽

Derek J. Bangs ◽

Lydia K. Lutes ◽

Shiao W. Chan ◽

Kristina M. Geiger ◽

...

Keyword(s):

T Cell ◽

Chronic Infection ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

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The Transcription Factor Foxo1 Controls Central-Memory CD8+ T Cell Responses to Infection

Immunity ◽

10.1016/j.immuni.2013.07.013 ◽

2013 ◽

Vol 39 (2) ◽

pp. 286-297 ◽

Cited By ~ 104

Author(s):

Myoungjoo V. Kim ◽

Weiming Ouyang ◽

Will Liao ◽

Michael Q. Zhang ◽

Ming O. Li

Keyword(s):

Transcription Factor ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Central Memory ◽

Cell Responses ◽

Memory Cd8 T Cell

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An unusual MHC molecule generates protective CD8+ T cell responses to chronic infection

10.1101/2020.02.03.932848 ◽

2020 ◽

Cited By ~ 1

Author(s):

A. Tsitsiklis ◽

D.J. Bangs ◽

L.K. Lutes ◽

S-W. Chan ◽

K. Geiger ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Chronic Infection ◽

Peptide Binding ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Elite Controller ◽

Murine Cytomegalovirus ◽

Cell Responses

AbstractThe CD8+ T cell response to the intracellular parasite Toxoplasma gondii varies dramatically between mouse strains, resulting in differences in control of the parasite. Protection in BALB/c mice can be attributed to an unusually strong and protective MHC-1 Ld-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 Ld molecule has limited peptide binding compared to conventional MHC molecules such as Kb or Db, which correlates with polymorphisms associated with “elite control” of HIV in humans. To investigate the link between the unusual MHC-1 molecule Ld and the generation of “elite controller” CD8+ T cell responses, we compared the GRA6-Ld specific T cell response to the well-studied OVA-Kb specific response, and demonstrated that GRA6-Ld specific T cells are significantly more protective and resistant to exhaustion in chronic T. gondii infection. To further investigate the connection between limited peptide presentation and robust T cell responses, we used CRISPR/Cas9 to generate mice with a point mutation (W97R) in the peptide-binding groove of Ld that results in broader peptide binding. We investigated the effect of this Ld W97R mutation on another robust Ld-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. This mutation leads to an increase in exhaustion markers in the IE1-Ld specific CD8+ T cell response. Our results indicate that limited peptide binding by MHC-1 Ld correlates with the development of robust and protective CD8+ T cell responses that may avoid exhaustion during chronic infection.

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