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Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8 + T cells, diminished interferon responses, and profound suppression of monocyte function. We also identify shifts in cytokine and chemokine levels in the sera of pregnant individuals, including a robust increase of interleukin-27, known to drive T cell exhaustion. Our findings reveal nuanced pregnancy-associated immune responses, which may contribute to the increased susceptibility of pregnant individuals to viral respiratory infection., Competing Interests: Declaration of interests A.-C.V. has a financial interest in 10X Genomics. The company designs and manufactures gene-sequencing technology for use in research, and such technology is being used in this research. A.-C.V.’s interests were reviewed by The Massachusetts General Hospital and Mass General Brigham in accordance with their institutional policies. J.R.H. consults for CJ CheilJedang and Interon Laboratories. A.G.E. consults for Mirvie, Inc. outside of this work and receives research funding from Merck Pharmaceuticals outside of this work. K.J.G. has served as a consultant for BillionToOne, Aetion, Roche, and Janssen Global Services outside of this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)