Effector and central memory T helper 2 cells respond differently to peptide immunotherapy

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• > vol. 111 no. 8
• > Karen J. Mackenzie,  E784–E793, doi: 10.1073/pnas.1316178111

1. Karen J. Mackenziea, 
2. Dominika J. Nowakowskaa,b,1, 
3. Melanie D. Leecha,b,1, 
4. Amanda J. McFarlanea,
5. Claire Wilsonc, 
6. Paul M. Fitcha,d, 
7. Richard A. O’Connora,b, 
8. Sarah E. M. Howiea, 
9. Jürgen Schwarzea,d, and
10. Stephen M. Andertona,b,2

Author Affiliations

1. Edited* by Philippa Marrack, Howard Hughes Medical Institute, National Jewish Health, Denver, CO, and approved January 22, 2014 (received for review August 27, 2013)

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Significance

Peptide immunotherapy (PIT) of ongoing allergy must control “memory” T helper 2 (Th2) cells. Memory T cells can be subdivided into effector memory T cells (Tem), which seem to be involved in immediate immune responses, and central memory T cells (Tcm), which are thought to provide long-term memory. We show that PIT can control allergic lung disease more effectively when the disease is driven by Tem Th2 cells, rather than by Tcm Th2 cells. PIT-treated Tcm remained more responsive to allergen, with a greater capacity to produce inflammatory Th2 cytokines in the lung. These were suppressed in PIT-treated Tem. These differences are important for clinical translation of PIT, because Tcm may be particularly dominant in some seasonal allergic conditions, such as hay fever.

Abstract

Peptide immunotherapy (PIT) offers realistic prospects for the treatment of allergic diseases, including allergic asthma. Much is understood of the behavior of naive T cells in response to PIT. However, treatment of patients with ongoing allergic disease requires detailed understanding of the responses of allergen-experienced T cells. CD62L expression by allergen-experienced T cells corresponds to effector/effector memory (CD62Llo) and central memory (CD62Lhi) subsets, which vary with allergen exposure (e.g., during, or out with, pollen season). The efficacy of PIT on different T helper 2 (Th2) cell memory populations is unknown. We developed a murine model of PIT in allergic airway inflammation (AAI) driven by adoptively transferred, traceable ovalbumin-experienced Th2 cells. PIT effectively suppressed AAI driven by unfractionated Th2 cells. Selective transfer of CD62Lhi and CD62Llo Th2 cells revealed that these two populations behaved differently from one another and from previously characterized (early deletional) responses of naive CD4+ T cells to PIT. Most notably, allergen-reactive CD62Llo Th2 cells were long-lived within the lung after PIT, before allergen challenge, in contrast to CD62Lhi Th2 cells. Despite this, PIT was most potent against CD62Llo Th2 cells in protecting from AAI, impairing their ability to produce Th2 cytokines, whereas this capacity was heightened in PIT-treated CD62Lhi Th2 cells. We conclude that Th2 cells do not undergo an early deletional form of tolerance after PIT. Moreover, memory Th2 subsets respond differently to PIT. These findings have implications for the clinical translation of PIT in different allergic scenarios.

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